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Handa T, Sugiyama T, Islam T, Johansen JP, Yanagawa Y, McHugh TJ, Okamoto H. The neural pathway from the superior subpart of the medial habenula to the interpeduncular nucleus suppresses anxiety. Mol Psychiatry 2025:10.1038/s41380-025-02964-8. [PMID: 40140491 DOI: 10.1038/s41380-025-02964-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 02/13/2025] [Accepted: 03/19/2025] [Indexed: 03/28/2025]
Abstract
The medial habenula (MHb) and its projection target, the interpeduncular nucleus (IPN), are highly conserved throughout vertebrate evolution. The MHb-IPN pathway connects the limbic system to the brainstem, consisting of subpathways that project in a topographically organized manner, and has been implicated in the regulation of fear and anxiety. Previous studies have revealed subregion-specific functions of the cholinergic ventral MHb and a substance P (SP)-positive (SP+) subpart of the dorsal MHb (dMHb). In contrast, the dMHb also contains another subpart, a SP-negative subpart known as the 'superior part of MHb (MHbS)'. Although the MHbS has been characterized from various aspects, e.g. distinct c-Fos responses to stressful events and electrophysiological properties compared to other subregions, many of its physiological functions remain to be investigated. Here we found that dopamine receptor D3 (DRD3)-Cre mice enable the labeling of the IPN subregion that receives the MHbS projection. The Cre-expressing somata within the lateral subnucleus of the IPN (LIPN) were concentrated in its most lateral area, which we refer to as the 'lateral subregion of the LIPN (lLIPN)'. This region is characterized by the absence of SP+ axons, in contrast to the medial subregion of the LIPN (mLIPN) innervated by the SP+ axons from the dorsal MHb. Chemogenetic activation and genetically induced synaptic silencing of the DRD3-Cre+ cells reduced and enhanced anxiety-like behavior, respectively. Moreover, c-Fos expression was increased in the lLIPN under an anxiogenic environment. These findings suggest that the MHbS-lLIPN pathway is activated under anxiogenic environments to counteract anxiety.
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Affiliation(s)
- Takehisa Handa
- Laboratory for Neural Circuit Dynamics of Decision Making, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
- Laboratory of Molecular Neuroscience, Medical Research Institute, Institute of Science Tokyo (formerly Tokyo Medical and Dental University), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
- Department of Psychiatry and Behavioral Sciences, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Taku Sugiyama
- Laboratory for Neural Circuit Dynamics of Decision Making, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
- Support Unit for Bio-Material Analysis, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Tanvir Islam
- Laboratory for Neural Circuit Dynamics of Decision Making, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
- Support Unit for Bio-Material Analysis, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Joshua P Johansen
- Laboratory for Neural Circuitry of Learning and Memory, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Yuchio Yanagawa
- Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, 3-39-15 Showacho, Maebashi, Gunma, 371-8511, Japan
| | - Thomas J McHugh
- Laboratory for Circuit and Behavioral Physiology, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Hitoshi Okamoto
- Laboratory for Neural Circuit Dynamics of Decision Making, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
- RIKEN CBS-Kao Collaboration Center, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
- Center for Advanced Biomedical Sciences, Faculty of Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku, Tokyo, 162-8489, Japan.
- Institute of Neuropsychiatry, 91 Bentencho, Shinjuku, Tokyo, 162-0851, Japan.
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Bastos-Gonçalves R, Coimbra B, Rodrigues AJ. The mesopontine tegmentum in reward and aversion: From cellular heterogeneity to behaviour. Neurosci Biobehav Rev 2024; 162:105702. [PMID: 38718986 DOI: 10.1016/j.neubiorev.2024.105702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/06/2024] [Accepted: 05/01/2024] [Indexed: 05/18/2024]
Abstract
The mesopontine tegmentum, comprising the pedunculopontine tegmentum (PPN) and the laterodorsal tegmentum (LDT), is intricately connected to various regions of the basal ganglia, motor systems, and limbic systems. The PPN and LDT can regulate the activity of different brain regions of these target systems, and in this way are in a privileged position to modulate motivated behaviours. Despite recent findings, the PPN and LDT have been largely overlooked in discussions about the neural circuits associated with reward and aversion. This review aims to provide a timely and comprehensive resource on past and current research, highlighting the PPN and LDT's connectivity and influence on basal ganglia and limbic, and motor systems. Seminal studies, including lesion, pharmacological, and optogenetic/chemogenetic approaches, demonstrate their critical roles in modulating reward/aversive behaviours. The review emphasizes the need for further investigation into the associated cellular mechanisms, in order to clarify their role in behaviour and contribution for different neuropsychiatric disorders.
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Affiliation(s)
- Ricardo Bastos-Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bárbara Coimbra
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - Ana João Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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Molas S, Freels TG, Zhao-Shea R, Lee T, Gimenez-Gomez P, Barbini M, Martin GE, Tapper AR. Dopamine control of social novelty preference is constrained by an interpeduncular-tegmentum circuit. Nat Commun 2024; 15:2891. [PMID: 38570514 PMCID: PMC10991551 DOI: 10.1038/s41467-024-47255-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 03/20/2024] [Indexed: 04/05/2024] Open
Abstract
Animals are inherently motivated to explore social novelty cues over familiar ones, resulting in a novelty preference (NP), although the behavioral and circuit bases underlying NP are unclear. Combining calcium and neurotransmitter sensors with fiber photometry and optogenetics in mice, we find that mesolimbic dopamine (DA) neurotransmission is strongly and predominantly activated by social novelty controlling bout length of interaction during NP, a response significantly reduced by familiarity. In contrast, interpeduncular nucleus (IPN) GABAergic neurons that project to the lateral dorsal tegmentum (LDTg) were inhibited by social novelty but activated during terminations with familiar social stimuli. Inhibition of this pathway during NP increased interaction and bout length with familiar social stimuli, while activation reduced interaction and bout length with novel social stimuli via decreasing DA neurotransmission. These data indicate interest towards novel social stimuli is encoded by mesolimbic DA which is dynamically regulated by an IPN→LDTg circuit to control NP.
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Affiliation(s)
- Susanna Molas
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA.
- Institute for Behavioral Genetics, University of Colorado Boulder 1480 30th St, Boulder, 80303, CO, USA.
- Department of Psychology and Neuroscience, University of Colorado Boulder 1905 Colorado Ave, Boulder, 80309, CO, USA.
| | - Timothy G Freels
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA
| | - Rubing Zhao-Shea
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA
| | - Timothy Lee
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA
| | - Pablo Gimenez-Gomez
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA
| | - Melanie Barbini
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA
| | - Gilles E Martin
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA
| | - Andrew R Tapper
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School 364 Plantation St, LRB, Worcester, 01605, MA, USA.
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Song R, Soler-Cedeño O, Xi ZX. Optical Intracranial Self-Stimulation (oICSS): A New Behavioral Model for Studying Drug Reward and Aversion in Rodents. Int J Mol Sci 2024; 25:3455. [PMID: 38542425 PMCID: PMC10970671 DOI: 10.3390/ijms25063455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/10/2024] [Accepted: 03/17/2024] [Indexed: 11/03/2024] Open
Abstract
Brain-stimulation reward, also known as intracranial self-stimulation (ICSS), is a commonly used procedure for studying brain reward function and drug reward. In electrical ICSS (eICSS), an electrode is surgically implanted into the medial forebrain bundle (MFB) in the lateral hypothalamus or the ventral tegmental area (VTA) in the midbrain. Operant lever responding leads to the delivery of electrical pulse stimulation. The alteration in the stimulation frequency-lever response curve is used to evaluate the impact of pharmacological agents on brain reward function. If a test drug induces a leftward or upward shift in the eICSS response curve, it implies a reward-enhancing or abuse-like effect. Conversely, if a drug causes a rightward or downward shift in the functional response curve, it suggests a reward-attenuating or aversive effect. A significant drawback of eICSS is the lack of cellular selectivity in understanding the neural substrates underlying this behavior. Excitingly, recent advancements in optical ICSS (oICSS) have facilitated the development of at least three cell type-specific oICSS models-dopamine-, glutamate-, and GABA-dependent oICSS. In these new models, a comparable stimulation frequency-lever response curve has been established and employed to study the substrate-specific mechanisms underlying brain reward function and a drug's rewarding versus aversive effects. In this review article, we summarize recent progress in this exciting research area. The findings in oICSS have not only increased our understanding of the neural mechanisms underlying drug reward and addiction but have also introduced a novel behavioral model in preclinical medication development for treating substance use disorders.
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Affiliation(s)
- Rui Song
- Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology (BIPT), 27th Taiping Road, Beijing 100850, China
| | - Omar Soler-Cedeño
- Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse (NIDA), Intramural Research Program (IRP), Baltimore, MD 21224, USA;
| | - Zheng-Xiong Xi
- Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse (NIDA), Intramural Research Program (IRP), Baltimore, MD 21224, USA;
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Olszewski NA, Tetteh-Quarshie S, Henderson BJ. Neuronal Excitability in the Medial Habenula and Ventral Tegmental Area Is Differentially Modulated by Nicotine Dosage and Menthol in a Sex-Specific Manner. eNeuro 2024; 11:ENEURO.0380-23.2024. [PMID: 38233142 PMCID: PMC10863631 DOI: 10.1523/eneuro.0380-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/15/2023] [Accepted: 01/10/2024] [Indexed: 01/19/2024] Open
Abstract
The medial habenula (MHb) has been identified as the limiting factor for nicotine intake and facilitating nicotine withdrawal. However, few studies have assessed MHb neuronal excitability in response to nicotine, and, currently, a gap in knowledge is present for finding behavioral correlates to neuronal excitability in the region. Moreover, no study to date has evaluated sex or nicotine dosage as factors of excitability in the MHb. Here, we utilized an e-vape self-administration (EVSA) model to determine differences between sexes with different nicotine dosages ± menthol. Following this paradigm, we employed patch-clamp electrophysiology to assess key metrics of MHb neuronal excitability in relation to behavioral endpoints. We observed female mice self-administered significantly more than males, regardless of dosage. We also observed a direct correlation between self-administration behavior and MHb excitability with low-dose nicotine + menthol in males. Conversely, a high dose of nicotine ± menthol yields an inverse correlation between excitability and self-administration behavior in males only. In addition, intrinsic excitability in the ventral tegmental area (VTA) does not track with the amount of nicotine self-administered. Rather, they correlate to the active/inactive discrimination of mice. Using fast-scan cyclic voltammetry, we also observed that dopamine release dynamics are linked to reinforcement-related behavior in males and motivation-related behaviors in females. These results point to a sex-specific difference in the activity of the MHb and VTA leading to distinct differences in self-administration behavior. His could lend evidence to clinical observations of smoking and nicotine-use behavior differing between males and females.
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Affiliation(s)
- Nathan A Olszewski
- Department of Biomedical Science and Research, Joan C. Edwards School of Medicine, Marshall University, Huntington 25703-1104, West Virginia
| | - Samuel Tetteh-Quarshie
- Department of Biomedical Science and Research, Joan C. Edwards School of Medicine, Marshall University, Huntington 25703-1104, West Virginia
| | - Brandon J Henderson
- Department of Biomedical Science and Research, Joan C. Edwards School of Medicine, Marshall University, Huntington 25703-1104, West Virginia
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Du Y, Zhou S, Ma C, Chen H, Du A, Deng G, Liu Y, Tose AJ, Sun L, Liu Y, Wu H, Lou H, Yu YQ, Zhao T, Lammel S, Duan S, Yang H. Dopamine release and negative valence gated by inhibitory neurons in the laterodorsal tegmental nucleus. Neuron 2023; 111:3102-3118.e7. [PMID: 37499661 DOI: 10.1016/j.neuron.2023.06.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/25/2023] [Accepted: 06/22/2023] [Indexed: 07/29/2023]
Abstract
GABAergic neurons in the laterodorsal tegmental nucleus (LDTGABA) encode aversion by directly inhibiting mesolimbic dopamine (DA). Yet, the detailed cellular and circuit mechanisms by which these cells relay unpleasant stimuli to DA neurons and regulate behavioral output remain largely unclear. Here, we show that LDTGABA neurons bidirectionally respond to rewarding and aversive stimuli in mice. Activation of LDTGABA neurons promotes aversion and reduces DA release in the lateral nucleus accumbens. Furthermore, we identified two molecularly distinct LDTGABA cell populations. Somatostatin-expressing (Sst+) LDTGABA neurons indirectly regulate the mesolimbic DA system by disinhibiting excitatory hypothalamic neurons. In contrast, Reelin-expressing LDTGABA neurons directly inhibit downstream DA neurons. The identification of separate GABAergic subpopulations in a single brainstem nucleus that relay unpleasant stimuli to the mesolimbic DA system through direct and indirect projections is critical for establishing a circuit-level understanding of how negative valence is encoded in the mammalian brain.
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Affiliation(s)
- Yonglan Du
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Siyao Zhou
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Chenyan Ma
- Division of Neurobiology, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Hui Chen
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Ana Du
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Guochuang Deng
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Yige Liu
- NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China; College of Forensic Science, School of Medicine, Xi'an Jiaotong University, No.76, Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Amanda J Tose
- Division of Neurobiology, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Li Sun
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Yijun Liu
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Hangjun Wu
- Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou 310058, China
| | - Huifang Lou
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Yan-Qin Yu
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Ting Zhao
- PKU-Nanjing Joint Institute of Translational Medicine, Nanjing 211800, China
| | - Stephan Lammel
- Division of Neurobiology, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Shumin Duan
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Hongbin Yang
- Department of Affiliated Mental Health Center of Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
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The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons. Mol Psychiatry 2023; 28:1027-1045. [PMID: 33990773 PMCID: PMC8590712 DOI: 10.1038/s41380-021-01137-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 04/08/2021] [Accepted: 04/19/2021] [Indexed: 01/07/2023]
Abstract
Dopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.
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Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice. Psychopharmacology (Berl) 2022; 239:3263-3276. [PMID: 36006414 DOI: 10.1007/s00213-022-06209-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/02/2022] [Indexed: 10/15/2022]
Abstract
RATIONALE Drug-induced potentiation of ventral tegmental area (VTA) glutamate signaling contributes critically to the induction of sensitization - an enhancement in responding to a drug following exposure which is thought to reflect neural changes underlying drug addiction. The laterodorsal tegmental nucleus (LDTg) provides one of several sources of glutamate input to the VTA. OBJECTIVE We used optogenetic techniques to test either the role of LDTg glutamate cells or their VTA afferents in the development of cocaine sensitization in male VGluT2::Cre mice. These were inhibited using halorhodopsin during each of five daily cocaine exposure injections. The expression of locomotor sensitization was assessed following a cocaine challenge injection 1-week later. RESULTS The locomotor sensitization seen in control mice was absent in male mice subjected to inhibition of LDTg-VTA glutamatergic circuitry during cocaine exposure. As sensitization of nucleus accumbens (NAcc) dopamine (DA) overflow is also induced by this drug exposure regimen, we used microdialysis to measure NAcc DA overflow on the test for sensitization. Consistent with the locomotor sensitization results, inhibition of LDTg glutamate afferents to the VTA during cocaine exposure prevented the sensitization of NAcc DA overflow observed in control mice. CONCLUSIONS These data identify the LDTg as the source of VTA glutamate critical for the development of cocaine sensitization in male mice. Accordingly, the LDTg may give rise to the synapses in the VTA at which glutamatergic plasticity, known to contribute to the enhancement of addictive behaviors, occurs.
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Liu C, Tose AJ, Verharen JPH, Zhu Y, Tang LW, de Jong JW, Du JX, Beier KT, Lammel S. An inhibitory brainstem input to dopamine neurons encodes nicotine aversion. Neuron 2022; 110:3018-3035.e7. [PMID: 35921846 PMCID: PMC9509462 DOI: 10.1016/j.neuron.2022.07.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 05/16/2022] [Accepted: 07/06/2022] [Indexed: 01/07/2023]
Abstract
Nicotine stimulates the dopamine (DA) system, which is essential for its rewarding effect. Nicotine is also aversive at high doses; yet, our knowledge about nicotine's dose-dependent effects on DA circuits remains limited. Here, we demonstrate that high doses of nicotine, which induce aversion-related behavior in mice, cause biphasic inhibitory and excitatory responses in VTA DA neurons that can be dissociated by distinct projections to lateral and medial nucleus accumben subregions, respectively. Guided by computational modeling, we performed a pharmacological investigation to establish that inhibitory effects of aversive nicotine involve desensitization of α4β2 and activation of α7 nicotinic acetylcholine receptors. We identify α7-dependent activation of upstream GABA neurons in the laterodorsal tegmentum (LDT) as a key regulator of heterogeneous DA release following aversive nicotine. Finally, inhibition of LDT GABA terminals in VTA prevents nicotine aversion. Together, our findings provide a mechanistic circuit-level understanding of nicotine's dose-dependent effects on reward and aversion.
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Affiliation(s)
- Christine Liu
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA
| | - Amanda J Tose
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA
| | - Jeroen P H Verharen
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA
| | - Yichen Zhu
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA
| | - Lilly W Tang
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA
| | - Johannes W de Jong
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA
| | - Jessica X Du
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA
| | - Kevin T Beier
- Department of Physiology and Biophysics, University of California Irvine, 825 Health Sciences Road, Med Sci D320, Irvine, CA 92697, USA
| | - Stephan Lammel
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, California, Berkeley, CA 94720, USA.
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10
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de Jong JW, Fraser KM, Lammel S. Mesoaccumbal Dopamine Heterogeneity: What Do Dopamine Firing and Release Have to Do with It? Annu Rev Neurosci 2022; 45:109-129. [PMID: 35226827 PMCID: PMC9271543 DOI: 10.1146/annurev-neuro-110920-011929] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Ventral tegmental area (VTA) dopamine (DA) neurons are often thought to uniformly encode reward prediction errors. Conversely, DA release in the nucleus accumbens (NAc), the prominent projection target of these neurons, has been implicated in reinforcement learning, motivation, aversion, and incentive salience. This contrast between heterogeneous functions of DA release versus a homogeneous role for DA neuron activity raises numerous questions regarding how VTA DA activity translates into NAc DA release. Further complicating this issue is increasing evidence that distinct VTA DA projections into defined NAc subregions mediate diverse behavioral functions. Here, we evaluate evidence for heterogeneity within the mesoaccumbal DA system and argue that frameworks of DA function must incorporate the precise topographic organization of VTA DA neurons to clarify their contribution to health and disease.
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Affiliation(s)
- Johannes W de Jong
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA;
| | - Kurt M Fraser
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA;
| | - Stephan Lammel
- Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA;
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11
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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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12
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Sustkova-Fiserova M, Charalambous C, Khryakova A, Certilina A, Lapka M, Šlamberová R. The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions. Int J Mol Sci 2022; 23:761. [PMID: 35054944 PMCID: PMC8776007 DOI: 10.3390/ijms23020761] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 01/27/2023] Open
Abstract
Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin's/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin's/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.
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Affiliation(s)
- Magdalena Sustkova-Fiserova
- Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague, Czech Republic; (C.C.); (A.K.); (A.C.); (M.L.)
| | - Chrysostomos Charalambous
- Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague, Czech Republic; (C.C.); (A.K.); (A.C.); (M.L.)
| | - Anna Khryakova
- Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague, Czech Republic; (C.C.); (A.K.); (A.C.); (M.L.)
| | - Alina Certilina
- Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague, Czech Republic; (C.C.); (A.K.); (A.C.); (M.L.)
| | - Marek Lapka
- Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague, Czech Republic; (C.C.); (A.K.); (A.C.); (M.L.)
| | - Romana Šlamberová
- Department of Physiology, Third Faculty of Medicine, Charles University, Ke Karlovu 4, 120 00 Prague, Czech Republic;
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13
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A non-canonical GABAergic pathway to the VTA promotes unconditioned freezing. Mol Psychiatry 2022; 27:4905-4917. [PMID: 36127430 PMCID: PMC9763111 DOI: 10.1038/s41380-022-01765-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/09/2022] [Accepted: 08/22/2022] [Indexed: 01/14/2023]
Abstract
Freezing is a conserved defensive behaviour that constitutes a major stress-coping mechanism. Decades of research have demonstrated a role of the amygdala, periaqueductal grey and hypothalamus as core actuators of the control of fear responses, including freezing. However, the role that other modulatory sites provide to this hardwired scaffold is not known. Here, we show that freezing elicited by exposure to electrical foot shocks activates laterodorsal tegmentum (LDTg) GABAergic neurons projecting to the VTA, without altering the excitability of cholinergic and glutamatergic LDTg neurons. Selective chemogenetic silencing of this inhibitory projection, but not other LDTg neuronal subtypes, dampens freezing responses but does not prevent the formation of conditioned fear memories. Conversely, optogenetic-activation of LDTg GABA terminals within the VTA drives freezing responses and elicits bradycardia, a common hallmark of freezing. Notably, this aversive information is subsequently conveyed from the VTA to the amygdala via a discrete GABAergic pathway. Hence, we unveiled a circuit mechanism linking LDTg-VTA-amygdala regions, which holds potential translational relevance for pathological freezing states such as post-traumatic stress disorders, panic attacks and social phobias.
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14
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Wills L, Ables JL, Braunscheidel KM, Caligiuri SPB, Elayouby KS, Fillinger C, Ishikawa M, Moen JK, Kenny PJ. Neurobiological Mechanisms of Nicotine Reward and Aversion. Pharmacol Rev 2022; 74:271-310. [PMID: 35017179 PMCID: PMC11060337 DOI: 10.1124/pharmrev.121.000299] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 08/24/2021] [Indexed: 12/27/2022] Open
Abstract
Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the rewarding actions of nicotine contained in tobacco that establish and maintain the smoking habit. nAChRs also regulate the aversive properties of nicotine, sensitivity to which decreases tobacco use and protects against tobacco use disorder. These opposing behavioral actions of nicotine reflect nAChR expression in brain reward and aversion circuits. nAChRs containing α4 and β2 subunits are responsible for the high-affinity nicotine binding sites in the brain and are densely expressed by reward-relevant neurons, most notably dopaminergic, GABAergic, and glutamatergic neurons in the ventral tegmental area. High-affinity nAChRs can incorporate additional subunits, including β3, α6, or α5 subunits, with the resulting nAChR subtypes playing discrete and dissociable roles in the stimulatory actions of nicotine on brain dopamine transmission. nAChRs in brain dopamine circuits also participate in aversive reactions to nicotine and the negative affective state experienced during nicotine withdrawal. nAChRs containing α3 and β4 subunits are responsible for the low-affinity nicotine binding sites in the brain and are enriched in brain sites involved in aversion, including the medial habenula, interpeduncular nucleus, and nucleus of the solitary tract, brain sites in which α5 nAChR subunits are also expressed. These aversion-related brain sites regulate nicotine avoidance behaviors, and genetic variation that modifies the function of nAChRs in these sites increases vulnerability to tobacco dependence and smoking-related diseases. Here, we review the molecular, cellular, and circuit-level mechanisms through which nicotine elicits reward and aversion and the adaptations in these processes that drive the development of nicotine dependence. SIGNIFICANCE STATEMENT: Tobacco use disorder in the form of habitual cigarette smoking or regular use of other tobacco-related products is a major cause of death and disease worldwide. This article reviews the actions of nicotine in the brain that contribute to tobacco use disorder.
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Affiliation(s)
- Lauren Wills
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Jessica L Ables
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Kevin M Braunscheidel
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Stephanie P B Caligiuri
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Karim S Elayouby
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Clementine Fillinger
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Masago Ishikawa
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Janna K Moen
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
| | - Paul J Kenny
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York
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15
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Coimbra B, Domingues AV, Soares‐Cunha C, Correia R, Pinto L, Sousa N, Rodrigues AJ. Laterodorsal tegmentum-ventral tegmental area projections encode positive reinforcement signals. J Neurosci Res 2021; 99:3084-3100. [PMID: 34374447 PMCID: PMC9541203 DOI: 10.1002/jnr.24931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/31/2021] [Accepted: 07/12/2021] [Indexed: 01/05/2023]
Abstract
The laterodorsal tegmentum (LDT) is a brainstem nucleus classically involved in REM sleep and attention, and that has recently been associated with reward-related behaviors, as it controls the activity of ventral tegmental area (VTA) dopaminergic neurons, modulating dopamine release in the nucleus accumbens. To further understand the role of LDT-VTA inputs in reinforcement, we optogenetically manipulated these inputs during different behavioral paradigms in male rats. We found that in a two-choice instrumental task, optical activation of LDT-VTA projections shifts and amplifies preference to the laser-paired reward in comparison to an otherwise equal reward; the opposite was observed with inhibition experiments. In a progressive ratio task, LDT-VTA activation boosts motivation, that is, enhances the willingness to work to get the reward associated with LDT-VTA stimulation; and the reverse occurs when inhibiting these inputs. Animals abolished preference if the reward was omitted, suggesting that LDT-VTA stimulation adds/decreases value to the stimulation-paired reward. In addition, we show that LDT-VTA optical activation induces robust preference in the conditioned and real-time place preference tests, while optical inhibition induces aversion. The behavioral findings are supported by electrophysiological recordings and c-fos immunofluorescence correlates in downstream target regions. In LDT-VTA ChR2 animals, we observed an increase in the recruitment of lateral VTA dopamine neurons and D1 neurons from nucleus accumbens core and shell; whereas in LDT-VTA NpHR animals, D2 neurons appear to be preferentially recruited. Collectively, these data show that the LDT-VTA inputs encode positive reinforcement signals and are important for different dimensions of reward-related behaviors.
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Affiliation(s)
- Bárbara Coimbra
- Life and Health Sciences Research Institute (ICVS)School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Ana Verónica Domingues
- Life and Health Sciences Research Institute (ICVS)School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Carina Soares‐Cunha
- Life and Health Sciences Research Institute (ICVS)School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Raquel Correia
- Life and Health Sciences Research Institute (ICVS)School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS)School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS)School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Ana João Rodrigues
- Life and Health Sciences Research Institute (ICVS)School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's–PT Government Associate LaboratoryBraga/GuimarãesPortugal
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16
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Shokri-Kojori E, Wang GJ, Volkow ND. Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men. Transl Psychiatry 2021; 11:445. [PMID: 34471102 PMCID: PMC8410787 DOI: 10.1038/s41398-021-01548-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 07/22/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [11C]raclopride-PET dataset to measure D2/3 receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (pFWE < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (pFWE < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.
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Affiliation(s)
- Ehsan Shokri-Kojori
- Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
| | - Gene-Jack Wang
- grid.94365.3d0000 0001 2297 5165Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD USA
| | - Nora D. Volkow
- grid.94365.3d0000 0001 2297 5165Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD USA
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17
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Hernandez NS, Weir VR, Ragnini K, Merkel R, Zhang Y, Mace K, Rich MT, Pierce RC, Schmidt HD. GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA. Mol Psychiatry 2021; 26:4394-4408. [PMID: 33257815 PMCID: PMC8164646 DOI: 10.1038/s41380-020-00957-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/27/2020] [Accepted: 11/06/2020] [Indexed: 11/09/2022]
Abstract
An emerging preclinical literature suggests that targeting central glucagon-like peptide-1 receptors (GLP-1Rs) may represent a novel approach to treating cocaine use disorder. However, the exact neural circuits and cell types that mediate the suppressive effects of GLP-1R agonists on cocaine-seeking behavior are largely unknown. The laterodorsal tegmental nucleus (LDTg) expresses GLP-1Rs and functions as a neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the primary source of central GLP-1, with midbrain and forebrain nuclei known to regulate cocaine-seeking behavior. The goal of this study was to characterize the role of LDTg GLP-1R-expressing neurons and their projections to the ventral tegmental area (VTA) in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we showed that administration of the GLP-1R agonist exendin-4 (Ex-4) directly into the LDTg significantly attenuated cocaine seeking at a dose that did not affect sucrose seeking, ad libitum food intake, or body weight. In addition, our studies revealed that selectively activating NTS-to-LDTg circuits attenuated cocaine seeking via a GLP-1R-dependent mechanism. We also demonstrated, for the first time, that GLP-1Rs are expressed primarily on GABAergic neurons in the LDTg and that the efficacy of Ex-4 to reduce cocaine seeking depends, in part, on activation of LDTg-to-VTA GABAergic projections. Taken together, these studies identify a central mechanism by which Ex-4 attenuates cocaine seeking and highlight GABAergic GLP-1R-expressing circuits in the midbrain as important anti-craving pathways in regulating cocaine craving-induced relapse.
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Affiliation(s)
- Nicole S. Hernandez
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Vanessa R. Weir
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Kael Ragnini
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Riley Merkel
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Yafang Zhang
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Kyla Mace
- Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Phildelphia, PA 19104
| | - Matthew T. Rich
- Brain Health Institute and Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854
| | - R. Christopher Pierce
- Brain Health Institute and Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854
| | - Heath D. Schmidt
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
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18
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Neurobiology of reward-related learning. Neurosci Biobehav Rev 2021; 124:224-234. [PMID: 33581225 DOI: 10.1016/j.neubiorev.2021.02.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 11/23/2022]
Abstract
A major goal in psychology is to understand how environmental stimuli associated with primary rewards come to function as conditioned stimuli, acquiring the capacity to elicit similar responses to those elicited by primary rewards. Our neurobiological model is predicated on the Hebbian idea that concurrent synaptic activity on the primary reward neural substrate-proposed to be ventral tegmental area (VTA) dopamine (DA) neurons-strengthens the synapses involved. We propose that VTA DA neurons receive both a strong unconditioned stimulus signal (acetylcholine stimulation of DA cells) from the primary reward capable of unconditionally activating DA cells and a weak stimulus signal (glutamate stimulation of DA cells) from the neutral stimulus. Through joint stimulation the weak signal is potentiated and capable of activating the VTA DA cells, eliciting a conditioned response. The learning occurs when this joint stimulation initiates intracellular second-messenger cascades resulting in enhanced glutamate-DA synapses. In this review we present evidence that led us to propose this model and the most recent evidence supporting it.
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19
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Vestlund J, Jerlhag E. The glucagon-like peptide-1 receptor agonist, exendin-4, reduces sexual interaction behaviors in a brain site-specific manner in sexually naïve male mice. Horm Behav 2020; 124:104778. [PMID: 32450068 DOI: 10.1016/j.yhbeh.2020.104778] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/04/2020] [Accepted: 05/18/2020] [Indexed: 01/26/2023]
Abstract
Besides reducing food intake and controlling energy balance, glucagon-like peptide-1 (GLP-1) suppresses the reinforcing properties of palatable foods and addictive drugs. This reduction in reward involves activation of GLP-1 receptors (GLP-1R) within areas processing natural and artificial rewards, including the laterodorsal tegmental area (LDTg), ventral tegmental area (VTA) and nucleus accumbens (NAc) shell. These areas are part of a neurocircuitry mediating reward from addictive drugs and natural rewards including sexual behaviors. The male sexual encounter with a female includes three different stages: a pre-sexual interaction phase with social behaviors, which is followed by a sexual interaction phase with mounting and intromission of the female, and ends with a post-sexual interaction phase characterized by self-grooming behaviors. Albeit GLP-1 modulates reward, the influence of GLP-1R activation on sexual interaction is unknown. Thus, we infused the GLP-1R agonist, exendin-4 (Ex4), into sub-regions of the reward neurocircuitry in sexually naïve male mice and recorded their novel interaction with an estrus female. We found that Ex4 into the LDTg, posterior VTA or NAc shell reduces pre-sexual interaction behaviors and activation of GLP-1R in the LDTg or posterior VTA decreases sexual interaction behaviors. Contrarily, Ex4 infusion into anterior VTA does not influence these behaviors. Furthermore, self-grooming behaviors are not influenced by activation of GLP-1R in the aforementioned areas. These data highlight that activation of GLP-1R in reward-related areas reduces different aspects of the sexual interaction chain and further supports a role of the GLP-1R in social behaviors.
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Affiliation(s)
- Jesper Vestlund
- Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Elisabet Jerlhag
- Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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20
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Cholinergic midbrain afferents modulate striatal circuits and shape encoding of action strategies. Nat Commun 2020; 11:1739. [PMID: 32269213 PMCID: PMC7142106 DOI: 10.1038/s41467-020-15514-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 03/13/2020] [Indexed: 02/06/2023] Open
Abstract
Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Acetylcholine in the striatum plays a pivotal role in such adaptation, and its release has been causally associated with the activity of cholinergic interneurons. Here we show that the midbrain, a previously unknown source of acetylcholine in the striatum, is a major contributor to cholinergic transmission in the striatal complex. Neurons of the pedunculopontine and laterodorsal tegmental nuclei synapse with striatal cholinergic interneurons and give rise to excitatory responses. Furthermore, they produce uniform inhibition of spiny projection neurons. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs the association of contingencies and the formation of habits in an instrumental task, and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons. These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum, where cholinergic interneurons are modulated by cholinergic neurons of the midbrain.
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21
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Kohlmeier KA, Polli FS. Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function. Front Synaptic Neurosci 2020; 12:3. [PMID: 32116639 PMCID: PMC7019863 DOI: 10.3389/fnsyn.2020.00003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/14/2020] [Indexed: 12/16/2022] Open
Abstract
The brainstem has traditionally been considered an area of the brain with autonomous control of mostly homeostatic functions such as heart rate, respiration, and the sleep and wakefulness state, which would preclude the necessity to exhibit the high degree of synaptic or cellular mechanisms of plasticity typical of regions of the brain responsible for flexible, executive control, such as the medial prefrontal cortex or the hippocampus. The perception that the brainstem does not share the same degree of flexibility to alter synaptic strength and/or wiring within local circuits makes intuitive sense, as it is not easy to understand how "soft wiring" would be an advantage when considering the importance of faithful and consistent performance of the homeostatic, autonomic functions that are controlled by the brainstem. However, many of the molecular and cellular requirements which underlie strengthening of synapses seen in brain regions involved in higher-level processing are present in brainstem nuclei, and recent research suggest that the view of the brainstem as "hard wired," with rigid and static connectivity and with unchanging synaptic strength, is outdated. In fact, information from studies within the last decades, including work conducted in our group, leads us to propose that the brainstem can dynamically alter synaptic proteins, and change synaptic connections in response to prenatal or postnatal stimuli, and this would likely alter functionality and output. This article reviews recent research that has provided information resulting in our revision of the view of the brainstem as static and non-changing by using as example recent information gleaned from a brainstem pontine nucleus, the laterodorsal tegmentum (LDT). The LDT has demonstrated mechanisms underlying synaptic plasticity, and plasticity has been exhibited in the postnatal LDT following exposure to drugs of abuse. Further, exposure of the brain during gestation to drugs of abuse results in alterations in development of signaling pathways in the LDT. As the LDT provides a high degree of innervation of mesoaccumbal and mesocortical circuits involved in salience, as well as thalamocortical circuits involved in control of arousal and orientation, changes in synaptic strength would be expected to alter output, which would significantly impact behavioral state, motivated behavior and directed attention. Further, alterations in developmental trajectory within the LDT following prenatal exposure to drugs of abuse would be expected to impact on later life expression of motivation and arousal.
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Affiliation(s)
- Kristi A. Kohlmeier
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
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22
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Jerlhag E. Alcohol-mediated behaviours and the gut-brain axis; with focus on glucagon-like peptide-1. Brain Res 2020; 1727:146562. [DOI: 10.1016/j.brainres.2019.146562] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/28/2019] [Accepted: 11/19/2019] [Indexed: 12/15/2022]
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23
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Fulcher N, Azzopardi E, De Oliveira C, Hudson R, Schormans AL, Zaman T, Allman BL, Laviolette SR, Schmid S. Deciphering midbrain mechanisms underlying prepulse inhibition of startle. Prog Neurobiol 2019; 185:101734. [PMID: 31863802 DOI: 10.1016/j.pneurobio.2019.101734] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/19/2019] [Accepted: 12/11/2019] [Indexed: 12/16/2022]
Abstract
Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. Deficits of PPI are a hallmark of schizophrenia and associated with several other psychiatric illnesses such as e.g. autism spectrum disorder, yet the mechanisms underlying PPI are still not fully understood. There is growing evidence contradicting the long-standing hypothesis that PPI is mediated by a short feed-forward midbrain circuitry including inhibitory cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the startle pathway. Here, we employed a chemogenetic approach to explore the involvement of the PPTg in general, and cholinergic neurons specifically, in PPI. Activation of inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in the PPTg by systemic administration of clozapine-N-oxide (CNO) disrupted PPI, confirming the involvement of the PPTg in PPI. In contrast, chemogenetic inhibition of specifically cholinergic PPTg neurons had no effect on PPI, but inhibited morphine-induced conditioned place preference (CPP) in the same animals, showing that the DREADDs were effective in modulating behavior. These findings support a functional role of the PPTg and/or neighboring structures in PPI in accordance with previous lesion studies, but also provide strong evidence against the hypothesis that specifically cholinergic PPTg neurons are involved in mediating PPI, implicating rather non-cholinergic midbrain neurons.
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Affiliation(s)
- Niveen Fulcher
- University of Western Ontario, Schulich School of Medicine & Dentistry, Neuroscience Graduate Program, London, ON, N6A 5C1 Canada
| | - Erin Azzopardi
- University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Anatomy & Cell Biology, London, ON, N6A 5C1 Canada
| | - Cleusa De Oliveira
- University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Anatomy & Cell Biology, London, ON, N6A 5C1 Canada
| | - Roger Hudson
- University of Western Ontario, Schulich School of Medicine & Dentistry, Neuroscience Graduate Program, London, ON, N6A 5C1 Canada
| | - Ashley L Schormans
- University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Anatomy & Cell Biology, London, ON, N6A 5C1 Canada
| | - Tariq Zaman
- University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Anatomy & Cell Biology, London, ON, N6A 5C1 Canada
| | - Brian L Allman
- University of Western Ontario, Schulich School of Medicine & Dentistry, Neuroscience Graduate Program, London, ON, N6A 5C1 Canada; University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Anatomy & Cell Biology, London, ON, N6A 5C1 Canada
| | - Steven R Laviolette
- University of Western Ontario, Schulich School of Medicine & Dentistry, Neuroscience Graduate Program, London, ON, N6A 5C1 Canada; University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Anatomy & Cell Biology, London, ON, N6A 5C1 Canada
| | - Susanne Schmid
- University of Western Ontario, Schulich School of Medicine & Dentistry, Neuroscience Graduate Program, London, ON, N6A 5C1 Canada; University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Anatomy & Cell Biology, London, ON, N6A 5C1 Canada.
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24
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Konanur VR, Hsu TM, Kanoski SE, Hayes MR, Roitman MF. Phasic dopamine responses to a food-predictive cue are suppressed by the glucagon-like peptide-1 receptor agonist Exendin-4. Physiol Behav 2019; 215:112771. [PMID: 31821815 DOI: 10.1016/j.physbeh.2019.112771] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/06/2019] [Accepted: 12/06/2019] [Indexed: 12/21/2022]
Abstract
Phasic dopamine activity is evoked by reliable predictors of food reward and plays a role in cue-triggered, goal-directed behavior. While this important signal is modulated by physiological state (e.g. hunger, satiety), the mechanisms by which physiological state is integrated by dopamine neurons is only beginning to be elucidated. Activation of central receptors for glucagon-like peptide-1 (GLP-1R) via long-acting agonists (e.g., Exendin-4) suppresses food intake and food-directed motivated behavior, in part, through action in regions with dopamine cell bodies, terminals, and/or neural populations that directly target the mesolimbic dopamine system. However, the effects of GLP-1R activation on cue-evoked, phasic dopamine signaling remain unknown. Here, in vivo fiber photometry was used to capture real-time signaling dynamics selectively from dopamine neurons in the ventral tegmental area of male and female transgenic (tyrosine hydroxylase-Cre; TH:Cre+) rats trained to associate an audio cue with the brief availability of a sucrose solution. Cue presentation evoked a brief spike in dopamine activity. Administration of Exendin-4 (Ex4; 0, 0.05, 0.1 μg) to the lateral ventricle both dose-dependently suppressed sucrose-directed behaviors and the magnitude of cue-evoked dopamine activity. Moreover, the amplitude of cue evoked dopamine activity was significantly correlated with subsequent sucrose-directed behaviors. While female rats exhibited overall reduced dopamine responses to the sucrose-paired cue relative to males, there was no significant interaction with Ex4. Together, these findings support a role for central GLP-1Rs in modulating a form of dopamine signaling that influences approach behavior and provide a potential mechanism whereby GLP-1 suppresses food-directed behaviors.
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Affiliation(s)
- Vaibhav R Konanur
- Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, IL, United States
| | - Ted M Hsu
- Department of Psychology, University of Illinois at Chicago, 1007W. Harrison St., Chicago, IL 60607-7137, United States
| | - Scott E Kanoski
- Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, CA, United States
| | - Matthew R Hayes
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Mitchell F Roitman
- Department of Psychology, University of Illinois at Chicago, 1007W. Harrison St., Chicago, IL 60607-7137, United States.
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25
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Polli FS, Kohlmeier KA. Alterations in NMDAR-mediated signaling within the laterodorsal tegmental nucleus are associated with prenatal nicotine exposure. Neuropharmacology 2019; 158:107744. [DOI: 10.1016/j.neuropharm.2019.107744] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/23/2019] [Accepted: 08/18/2019] [Indexed: 12/18/2022]
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26
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Coimbra B, Soares-Cunha C, Vasconcelos NAP, Domingues AV, Borges S, Sousa N, Rodrigues AJ. Role of laterodorsal tegmentum projections to nucleus accumbens in reward-related behaviors. Nat Commun 2019; 10:4138. [PMID: 31515512 PMCID: PMC6742663 DOI: 10.1038/s41467-019-11557-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 07/15/2019] [Indexed: 11/13/2022] Open
Abstract
The laterodorsal tegmentum (LDT) is associated with reward considering that it modulates VTA neuronal activity, but recent anatomical evidence shows that the LDT also directly projects to nucleus accumbens (NAc). We show that the majority of LDT-NAc inputs are cholinergic, but there is also GABAergic and glutamatergic innervation; activation of LDT induces a predominantly excitatory response in the NAc. Non-selective optogenetic activation of LDT-NAc projections in rats enhances motivational drive and shifts preference to an otherwise equal reward; whereas inhibition of these projections induces the opposite. Activation of these projections also induces robust place preference. In mice, specific activation of LDT-NAc cholinergic inputs (but not glutamatergic or GABAergic) is sufficient to shift preference, increase motivation, and drive positive reinforcement in different behavioral paradigms. These results provide evidence that LDT-NAc projections play an important role in motivated behaviors and positive reinforcement, and that distinct neuronal populations differentially contribute for these behaviors.
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Affiliation(s)
- Bárbara Coimbra
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Carina Soares-Cunha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nivaldo A P Vasconcelos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Department of Biomedical Engineering, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
| | - Ana Verónica Domingues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Sónia Borges
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
- Clinical Academic Center (2CA-Braga), Braga, Portugal.
| | - Ana João Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
- Clinical Academic Center (2CA-Braga), Braga, Portugal.
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27
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Bueno D, Lima LB, Souza R, Gonçalves L, Leite F, Souza S, Furigo IC, Donato J, Metzger M. Connections of the laterodorsal tegmental nucleus with the habenular‐interpeduncular‐raphe system. J Comp Neurol 2019; 527:3046-3072. [DOI: 10.1002/cne.24729] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 06/06/2019] [Accepted: 06/07/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Debora Bueno
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
| | - Leandro B. Lima
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
| | - Rudieri Souza
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
| | - Luciano Gonçalves
- Department of Human AnatomyFederal University of the Triângulo Mineiro Uberaba Brazil
| | - Fernanda Leite
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
| | - Stefani Souza
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
| | - Isadora C. Furigo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
| | - Martin Metzger
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo Brazil
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28
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Brain region specific glucagon-like peptide-1 receptors regulate alcohol-induced behaviors in rodents. Psychoneuroendocrinology 2019; 103:284-295. [PMID: 30771711 DOI: 10.1016/j.psyneuen.2019.02.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/04/2019] [Accepted: 02/06/2019] [Indexed: 01/03/2023]
Abstract
Glucagon-like peptide 1 (GLP-1), an incretin hormone that reduces food intake, was recently established as a novel regulator of alcohol-mediated behaviors. Clinically available analogues pass freely into the brain, but the mechanisms underlying GLP-1-modulated alcohol reward remains largely unclear. GLP-1 receptors (GLP-1R) are expressed throughout the nuclei of importance for acute and chronic effects of alcohol, such as the laterodorsal tegmental area (LDTg), the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We therefore evaluated the effects of bilateral infusion of the GLP-1R agonist exendin-4 (Ex4) into NAc shell, anterior (aVTA), posterior (pVTA) or LDTg on the acute alcohol-induced locomotor stimulation and memory of alcohol reward in the conditioned place preference (CPP) model in mice, as well as on alcohol intake in rats consuming high amounts of alcohol for 12 weeks. Ex4 into the NAc shell blocks alcohol-induced locomotor stimulation and memory of alcohol reward as well as decreases alcohol intake. The GLP-1R expression in NAc is elevated in high compared to low alcohol-consuming rats. On the contrary, GLP-1R activation in the aVTA does not modulate alcohol-induced behaviors. Ex4 into the pVTA prevents alcohol-induced locomotor simulation, but does neither modulate CPP-dependent alcohol memory nor alcohol intake. Intra-LDTg-Ex4 attenuates alcohol-induced locomotor stimulation and reduces alcohol intake, but does not affect memory of alcohol reward. Collectively, these data provide additional knowledge of the functional role of GLP-1R in reward-related areas for alcohol-mediated behaviors and further support GLP-1R as a potential treatment target for alcohol use disorder.
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29
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Kami K, Tajima F, Senba E. Activation of mesolimbic reward system via laterodorsal tegmental nucleus and hypothalamus in exercise-induced hypoalgesia. Sci Rep 2018; 8:11540. [PMID: 30069057 PMCID: PMC6070570 DOI: 10.1038/s41598-018-29915-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 07/20/2018] [Indexed: 11/08/2022] Open
Abstract
Ventral tegmental area (VTA) dopamine (DA) neurons are the primary source of dopamine in target structures that constitute the mesolimbic reward system. Previous studies demonstrated that voluntary wheel running (VWR) by neuropathic pain (NPP) model mice produces exercise-induced hypoalgesia (EIH), and that activation of mesolimbic reward system may lead to EIH. However, the neuronal mechanism by which the mesolimbic reward system is activated by VWR is unknown. Here, we found that VWR produces EIH effects and reverses the marked reduction in activated lateral VTA (lVTA)-DA neurons induced by NPP. The proportions of activated laterodorsal tegmental nucleus (LDT)-cholinergic and lateral hypothalamus-orexin neurons were significantly enhanced by VWR. Retrograde tracing and dual immunostaining revealed that VWR activates lVTA-projecting LDT-cholinergic/non-cholinergic and lateral hypothalamic area (LHA)-orexin/non-orexin neurons. Therefore, EIH effects may be produced, at least in part, by activation of the mesolimbic reward system via activation of LDT and LHA neurons.
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Affiliation(s)
- Katsuya Kami
- Department of Rehabilitation Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama, 641-8509, Japan.
| | - Fumihiro Tajima
- Department of Rehabilitation Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama, 641-8509, Japan
| | - Emiko Senba
- Department of Rehabilitation Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama, 641-8509, Japan
- Department of Physical Therapy, Osaka Yukioka College of Health Science, 1-1-41 Sojiji, Ibaraki City, Osaka, 567-0801, Japan
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30
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Kaneda K. Neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus contributes to the development of cocaine addiction. Eur J Neurosci 2018; 50:2239-2246. [DOI: 10.1111/ejn.13962] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/20/2018] [Accepted: 05/04/2018] [Indexed: 11/27/2022]
Affiliation(s)
- Katsuyuki Kaneda
- Laboratory of Molecular Pharmacology Institute of Medical, Pharmaceutical and Health Sciences Kanazawa University Kanazawa 920‐1192 Japan
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31
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Wolfman SL, Gill DF, Bogdanic F, Long K, Al-Hasani R, McCall JG, Bruchas MR, McGehee DS. Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum. Nat Commun 2018; 9:2710. [PMID: 30006624 PMCID: PMC6045623 DOI: 10.1038/s41467-018-04654-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 05/04/2018] [Indexed: 11/24/2022] Open
Abstract
Nicotine use can lead to dependence through complex processes that are regulated by both its rewarding and aversive effects. Recent studies show that aversive nicotine doses activate excitatory inputs to the interpeduncular nucleus (IPN) from the medial habenula (MHb), but the downstream targets of the IPN that mediate aversion are unknown. Here we show that IPN projections to the laterodorsal tegmentum (LDTg) are GABAergic using optogenetics in tissue slices from mouse brain. Selective stimulation of these IPN axon terminals in LDTg in vivo elicits avoidance behavior, suggesting that these projections contribute to aversion. Nicotine modulates these synapses in a concentration-dependent manner, with strong enhancement only seen at higher concentrations that elicit aversive responses in behavioral tests. Optogenetic inhibition of the IPN-LDTg connection blocks nicotine conditioned place aversion, suggesting that the IPN-LDTg connection is a critical part of the circuitry that mediates the aversive effects of nicotine.
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Affiliation(s)
- Shannon L Wolfman
- Committee on Neurobiology, University of Chicago, Chicago, IL, 60637, USA
| | - Daniel F Gill
- Committee on Neurobiology, University of Chicago, Chicago, IL, 60637, USA
| | - Fili Bogdanic
- Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL, 60637, USA
| | - Katie Long
- Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL, 60637, USA
| | - Ream Al-Hasani
- St. Louis College of Pharmacy, Center for Clinical Pharmacology and Division of Basic Research of the Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Jordan G McCall
- St. Louis College of Pharmacy, Center for Clinical Pharmacology and Division of Basic Research of the Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Division of Basic Research, Department of Anesthesiology, Washington University Pain Center, St. Louis, MO, 63110, USA
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Michael R Bruchas
- Division of Basic Research, Department of Anesthesiology, Washington University Pain Center, St. Louis, MO, 63110, USA
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Daniel S McGehee
- Committee on Neurobiology, University of Chicago, Chicago, IL, 60637, USA.
- Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL, 60637, USA.
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32
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Zucca A, Zucca S, Wickens J. Cholinergic mechanisms in adaptive behaviour. Eur J Neurosci 2018; 47:1146-1147. [PMID: 29770984 DOI: 10.1111/ejn.13926] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Aya Zucca
- Okinawa Institute for Science and Technology, Okinawa, Japan
| | - Stefano Zucca
- Okinawa Institute for Science and Technology, Okinawa, Japan
| | - Jeff Wickens
- Okinawa Institute for Science and Technology, Okinawa, Japan
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33
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Luquin E, Huerta I, Aymerich MS, Mengual E. Stereological Estimates of Glutamatergic, GABAergic, and Cholinergic Neurons in the Pedunculopontine and Laterodorsal Tegmental Nuclei in the Rat. Front Neuroanat 2018; 12:34. [PMID: 29867374 PMCID: PMC5958217 DOI: 10.3389/fnana.2018.00034] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 04/16/2018] [Indexed: 01/29/2023] Open
Abstract
The pedunculopontine tegmental nucleus (PPN) and laterodorsal tegmental nucleus (LDT) are functionally associated brainstem structures implicated in behavioral state control and sensorimotor integration. The PPN is also involved in gait and posture, while the LDT plays a role in reward. Both nuclei comprise characteristic cholinergic neurons intermingled with glutamatergic and GABAergic cells whose absolute numbers in the rat have been only partly established. Here we sought to determine the complete phenotypical profile of each nucleus to investigate potential differences between them. Counts were obtained using stereological methods after the simultaneous visualization of cholinergic and either glutamatergic or GABAergic cells. The two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67, were separately analyzed. Dual in situ hybridization revealed coexpression of GAD65 and GAD67 mRNAs in ∼90% of GAD-positive cells in both nuclei; thus, the estimated mean numbers of (1) cholinergic, (2) glutamatergic, and (3) GABAergic cells in PPN and LDT, respectively, were (1) 3,360 and 3,650; (2) 5,910 and 5,190; and (3) 4,439 and 7,599. These data reveal significant differences between PPN and LDT in their relative phenotypical composition, which may underlie some of the functional differences observed between them. The estimation of glutamatergic cells was significantly higher in the caudal PPN, supporting the reported functional rostrocaudal segregation in this nucleus. Finally, a small subset of cholinergic neurons (8% in PPN and 5% in LDT) also expressed the glutamatergic marker Vglut2, providing anatomical evidence for a potential corelease of transmitters at specific target areas.
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Affiliation(s)
- Esther Luquin
- Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Ibone Huerta
- Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - María S Aymerich
- Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, Spain
| | - Elisa Mengual
- Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain
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34
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Polli FS, Kohlmeier KA. Prenatal nicotine exposure alters postsynaptic AMPA receptors and glutamate neurotransmission within the laterodorsal tegmentum (LDT) of juvenile mice. Neuropharmacology 2018; 137:71-85. [PMID: 29751228 DOI: 10.1016/j.neuropharm.2018.04.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 04/20/2018] [Accepted: 04/22/2018] [Indexed: 02/06/2023]
Abstract
Despite dissemination of information regarding the harm on fetal development of smoking while pregnant, the number of pregnancies associated with nicotine exposure appears to have stagnated. Presence of nicotine during neural formulation is associated with a higher susceptibility of drug dependence, suggesting an altered development of neurons in circuits involved in saliency and motivation. The laterodorsal tegmental nucleus (LDT) plays a role in coding stimuli valence via afferents to mesolimbic nuclei. Accordingly, alterations in development of neural mechanisms in the LDT could be involved in vulnerability to drug dependency. Therefore, we examined the effect of prenatal nicotine exposure (PNE) on glutamatergic functioning of LDT neurons in mouse brain slices using whole-cell, patch clamp concurrent with fluorescence-based calcium imaging. PNE was associated with larger amplitudes of AMPA-induced currents, and greater AMPA-mediated rises in intracellular calcium. AMPA/NMDA ratios and the AMPA-current rectification index were lower and higher, respectively, consistent with changes in the functionality of AMPA receptors in the PNE, which was substantiated by a greater inhibition of evoked and spontaneous glutamatergic synaptic events by a selective inhibitor of GluA2-lacking AMPA receptors. Paired pulse ratios showed a decreased probability of glutamate release from presynaptic inputs, and fluorescent imaging indicated a decreased action potential-dependent calcium increase associated with PNE. When taken together, our data suggest that PNE alters LDT glutamatergic functioning, which could alter output to mesolimbic targets. Such an alteration could play a role in altered coding of relevancy of drug stimuli that could enhance risk for development of drug dependency.
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Affiliation(s)
- Filip S Polli
- Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
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Zhang C, Liu X, Zhou P, Zhang J, He W, Yuan TF. Cholinergic tone in ventral tegmental area: Functional organization and behavioral implications. Neurochem Int 2018; 114:127-133. [DOI: 10.1016/j.neuint.2018.02.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 01/20/2018] [Accepted: 02/01/2018] [Indexed: 11/29/2022]
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Drive and Reinforcement Circuitry in the Brain: Origins, Neurotransmitters, and Projection Fields. Neuropsychopharmacology 2018; 43:680-689. [PMID: 28984293 PMCID: PMC5809792 DOI: 10.1038/npp.2017.228] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 08/08/2017] [Accepted: 09/13/2017] [Indexed: 01/07/2023]
Abstract
Brain stimulation has identified two central subsets of stimulation sites with motivational relevance. First, there is a large and disperse set of sites where stimulation is reinforcing, increasing the frequency of the responses it follows, and second, a much more restricted set of sites where-along with reinforcement-stimulation also has drive-like effects, instigating feeding, copulation, predation, and other motivated acts in otherwise sated or peaceful animals. From this work a dispersed but synaptically interconnected network of reinforcement circuitry is emerging: it includes afferents to the ventral tegmental area and substantia nigra; the dopamine systems themselves; glutamatergic afferents to the striatum; and one of two dopamine-receptor-expressing efferent pathways of the striatum. Stimulation of a limited subset of these sites, including descending inhibitory medial forebrain bundle fibers, induces both feeding and reinforcement, and suggests the possibility of a subset of fibers where stimulation has both drive-like and reinforcing effects. This review stresses the common findings of sites and connectivity between electrical and optogenetic studies of core drive and reinforcement sites. By doing so, it suggests the biological importance of optogenetic follow-up of less-publicized electrical stimulation findings. Such studies promise not only information about origins, neurotransmitters, and connectivity of related networks, by covering more sensory and at least one putative motor component they also promote a much deeper understanding of the breadth of motivational function.
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Hsu TM, McCutcheon JE, Roitman MF. Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons. Front Psychiatry 2018; 9:410. [PMID: 30233430 PMCID: PMC6129766 DOI: 10.3389/fpsyt.2018.00410] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/13/2018] [Indexed: 01/08/2023] Open
Abstract
Motivated behaviors are often initiated in response to perturbations of homeostasis. Indeed, animals and humans have fundamental drives to procure (appetitive behaviors) and eventually ingest (consummatory behaviors) substances based on deficits in body fluid (e.g., thirst) and energy balance (e.g., hunger). Consumption, in turn, reinforces motivated behavior and is therefore considered rewarding. Over the years, the constructs of homeostatic (within the purview of the hypothalamus) and reward (within the purview of mesolimbic circuitry) have been used to describe need-based vs. need-free consumption. However, many experiments have demonstrated that mesolimbic circuits and "higher-order" brain regions are also profoundly influenced by changes to physiological state, which in turn generate behaviors that are poised to maintain homeostasis. Mesolimbic pathways, particularly dopamine neurons of the ventral tegmental area (VTA) and their projections to nucleus accumbens (NAc), can be robustly modulated by a variety of energy balance signals, including post-ingestive feedback relaying nutrient content and hormonal signals reflecting hunger and satiety. Moreover, physiological states can also impact VTA-NAc responses to non-nutritive rewards, such as drugs of abuse. Coupled with recent evidence showing hypothalamic structures are modulated in anticipation of replenished need, classic boundaries between circuits that convey perturbations in homeostasis and those that drive motivated behavior are being questioned. In the current review, we examine data that have revealed the importance of mesolimbic dopamine neurons and their downstream pathways as a dynamic neurobiological mechanism that provides an interface between physiological state, perturbations to homeostasis, and reward-seeking behaviors.
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Affiliation(s)
- Ted M Hsu
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
| | - James E McCutcheon
- Department of Neuroscience, Psychology and Behavior, University of Leicester, Leicester, United Kingdom
| | - Mitchell F Roitman
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
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Abreu-Villaça Y, Manhães AC, Krahe TE, Filgueiras CC, Ribeiro-Carvalho A. Tobacco and alcohol use during adolescence: Interactive mechanisms in animal models. Biochem Pharmacol 2017; 144:1-17. [DOI: 10.1016/j.bcp.2017.06.113] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 06/05/2017] [Indexed: 12/13/2022]
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Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons. Neurosci Biobehav Rev 2017; 83:72-82. [PMID: 28951251 DOI: 10.1016/j.neubiorev.2017.09.022] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Revised: 08/12/2017] [Accepted: 09/21/2017] [Indexed: 01/06/2023]
Abstract
Opioids, such as morphine or heroin, increase forebrain dopamine (DA) release and locomotion, and support the acquisition of conditioned place preference (CPP) or self-administration. The most sensitive sites for these opioid effects in rodents are in the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg). Opioid inhibition of GABA neurons in these sites is hypothesized to lead to arousing and rewarding effects through disinhibition of VTA DA neurons. We review findings that the laterodorsal tegmental (LDTg) and pedunculopontine tegmental (PPTg) nuclei, which each contain cholinergic, GABAergic, and glutamatergic cells, are important for these effects. LDTg and/or PPTg cholinergic inputs to VTA mediate opioid-induced locomotion and DA activation via VTA M5 muscarinic receptors. LDTg and/or PPTg cholinergic inputs to RMTg also modulate opioid-induced locomotion. Lesions or inhibition of LDTg or PPTg neurons reduce morphine-induced increases in forebrain DA release, acquisition of morphine CPP or self-administration. We propose a circuit model that links VTA and RMTg GABA with LDTg and PPTg neurons critical for DA-dependent opioid effects in drug-naïve rodents.
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Mena-Segovia J, Bolam JP. Rethinking the Pedunculopontine Nucleus: From Cellular Organization to Function. Neuron 2017; 94:7-18. [PMID: 28384477 DOI: 10.1016/j.neuron.2017.02.027] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 02/03/2017] [Accepted: 02/15/2017] [Indexed: 12/21/2022]
Abstract
The pedunculopontine nucleus (PPN) has long been considered an interface between the basal ganglia and motor systems, and its ability to regulate arousal states puts the PPN in a key position to modulate behavior. Despite the large amount of data obtained over recent decades, a unified theory of its function is still incomplete. By putting together classical concepts and new evidence that dissects the influence of its different neuronal subtypes on their various targets, we propose that the PPN and, in particular, cholinergic neurons have a central role in updating the behavioral state as a result of changes in environmental contingencies. Such a function is accomplished by a combined mechanism that simultaneously restrains ongoing obsolete actions while it facilitates new contextual associations.
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Affiliation(s)
- Juan Mena-Segovia
- Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ 07102, USA.
| | - J Paul Bolam
- MRC Brain Network Dynamics Unit, University of Oxford, Oxford OX1 3TH, UK
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Janickova H, Prado VF, Prado MAM, El Mestikawy S, Bernard V. Vesicular acetylcholine transporter (VAChT) over-expression induces major modifications of striatal cholinergic interneuron morphology and function. J Neurochem 2017. [DOI: 10.1111/jnc.14105] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Helena Janickova
- Department of Physiology and Pharmacology and Department of Anatomy & Cell Biology; Robarts Research Institute; Molecular Medicine Laboratories; The University of Western Ontario; London Ontario Canada
| | - Vania F. Prado
- Department of Physiology and Pharmacology and Department of Anatomy & Cell Biology; Robarts Research Institute; Molecular Medicine Laboratories; The University of Western Ontario; London Ontario Canada
| | - Marco A. M. Prado
- Department of Physiology and Pharmacology and Department of Anatomy & Cell Biology; Robarts Research Institute; Molecular Medicine Laboratories; The University of Western Ontario; London Ontario Canada
| | - Salah El Mestikawy
- Sorbonne Universités; Université Pierre et Marie Curie UM 119 - CNRS UMR 8246 - INSERM U1130; Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS); Paris France
- Department of Psychiatry; Douglas Mental Health University Institute; McGill University; Montreal Canada
| | - Véronique Bernard
- Sorbonne Universités; Université Pierre et Marie Curie UM 119 - CNRS UMR 8246 - INSERM U1130; Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS); Paris France
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Steidl S, O'Sullivan S, Pilat D, Bubula N, Brown J, Vezina P. Operant responding for optogenetic excitation of LDTg inputs to the VTA requires D1 and D2 dopamine receptor activation in the NAcc. Behav Brain Res 2017; 333:161-170. [PMID: 28666837 DOI: 10.1016/j.bbr.2017.06.045] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/09/2017] [Accepted: 06/26/2017] [Indexed: 01/22/2023]
Abstract
Behavioral studies in rats and mice indicate that laterodorsal tegmental nucleus (LDTg) inputs to the ventral tegmental area (VTA) importantly contribute to reward function. Further evidence from anesthetized rat and mouse preparations suggests that these LTDg inputs may exert this effect by regulating mesolimbic dopamine (DA) signaling. Direct evidence supporting this possibility remains lacking however. To address this lack, rat LDTg neurons were transfected with adeno-associated viral vectors encoding channelrhodopsin2 and eYFP (ChR2) or eYFP alone (eYFP) and rats were subsequently trained to lever press for intracranial self-stimulation (ICSS) of the inputs of these neurons to the VTA. First, we found that DA overflow in the forebrain nucleus accumbens (NAcc) increased maximally during ICSS to approximately 240% of baseline levels in ChR2, but not in eYFP, rats. Based on these findings, we next tested the contribution of NAcc D1 and D2 DA receptors to the reinforcing effects of optogenetic excitation of LDTg inputs to the VTA. Microinjecting SCH23390 or raclopride, D1 and D2 DA receptor antagonists respectively, into the NAcc significantly reduced operant responding for this stimulation. Together these results demonstrate for the first time that optogenetic ICSS of LDTg inputs to the VTA increases DA overflow in the NAcc and requires activation of D1 and D2 DA receptors in this site.
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Affiliation(s)
- Stephan Steidl
- Department of Psychology, Loyola University Chicago,1032 West Sheridan Road, Chicago, IL 60626, United States.
| | - Shannon O'Sullivan
- Department of Psychology, Loyola University Chicago,1032 West Sheridan Road, Chicago, IL 60626, United States
| | - Dustin Pilat
- Department of Psychology, Loyola University Chicago,1032 West Sheridan Road, Chicago, IL 60626, United States
| | - Nancy Bubula
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, 5481 South Maryland Avenue, Chicago, IL 60637, United States
| | - Jason Brown
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, 5481 South Maryland Avenue, Chicago, IL 60637, United States
| | - Paul Vezina
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, 5481 South Maryland Avenue, Chicago, IL 60637, United States
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Cardozo Pinto DF, Lammel S. Viral vector strategies for investigating midbrain dopamine circuits underlying motivated behaviors. Pharmacol Biochem Behav 2017; 174:23-32. [PMID: 28257849 DOI: 10.1016/j.pbb.2017.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/07/2017] [Accepted: 02/23/2017] [Indexed: 12/21/2022]
Abstract
Midbrain dopamine (DA) neurons have received significant attention in brain research because of their central role in reward processing and their dysfunction in neuropsychiatric disorders such as Parkinson's disease, drug addiction, depression and schizophrenia. Until recently, it has been thought that DA neurons form a homogeneous population whose primary function is the computation of reward prediction errors. However, through the implementation of viral vector strategies, an unexpected complexity and diversity has been revealed at the anatomical, molecular and functional level. In this review, we discuss recent viral vector approaches that have been leveraged to dissect how different circuits involving distinct DA neuron subpopulations may contribute to the role of DA in reward- and aversion-related behaviors. We focus on studies that have used cell type- and projection-specific optogenetic manipulations, discuss the strengths and limitations of each approach, and critically examine emergent organizational principles that have led to a reclassification of midbrain DA neurons.
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Affiliation(s)
- Daniel F Cardozo Pinto
- Department of Molecular and Cell Biology, University of California, Berkeley, 142 Life Science Addition #3200, CA 94720, USA
| | - Stephan Lammel
- Department of Molecular and Cell Biology, University of California, Berkeley, 142 Life Science Addition #3200, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, 142 Life Science Addition #3200, CA 94720, USA.
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Morales M, Margolis EB. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat Rev Neurosci 2017; 18:73-85. [DOI: 10.1038/nrn.2016.165] [Citation(s) in RCA: 594] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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