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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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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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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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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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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: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [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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Abburi C, McDaid J. Ethanol interaction with α3β4 nicotinic acetylcholine receptors in neurons of the laterodorsal tegmentum. Alcohol Clin Exp Res 2021; 45:2495-2505. [PMID: 34625982 DOI: 10.1111/acer.14727] [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: 03/30/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Nicotinic acetylcholine receptors (nAChRs) play a key role in the rewarding effects of ethanol (EtOH), and while several nAChR subtypes have been implicated, attention has recently shifted to a role for the α3β4 nAChR. The laterodorsal tegmental nucleus (LDTg), a brainstem cholinergic nucleus that sends excitatory projections to the ventral tegmental area, is an Integral part of the brain reward pathway. Here we investigate a potential role for LDTg α3β4 nAChRs in EtOH self-administration and reward. METHODS Sprague-Dawley rats were given ad libitum access to a 20% EtOH solution, as part of a two-bottle choice paradigm. Approximately 1 week after removal of EtOH access, we measured LDTg α3β4 nAChR current responses to focal application of acetylcholine (ACh), using whole-cell patch clamp electrophysiology recordings in acute brain slices. In addition, we used whole-cell electrophysiology to assess the acute effects of EtOH on the sensitivity of LDTg α3β4 nAChRs. RESULTS Focal application of ACh onto LDTg neurons resulted in large α3β4 nAChR-mediated inward currents, the magnitude of which showed a positive correlation with levels of EtOH self-administration. In addition, using brain slices taken from EtOH-naïve rats, bath application of EtOH resulted in a moderate potentiation of LDTg α3β4 nAChR sensitivity. CONCLUSIONS Using a rat model, increased α3β4 nAChR function was associated with greater EtOH self-administration, with α3β4 nAChR function also acutely potentiated by EtOH. Assuming that similar findings apply to humans, the α3β4 nAChR could be a therapeutic target in the treatment of EtOH use disorder.
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Affiliation(s)
- Chandrika Abburi
- Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois, 60637, USA
| | - John McDaid
- Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois, 60637, USA
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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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Wang S, Leri F, Rizvi SJ. Anhedonia as a central factor in depression: Neural mechanisms revealed from preclinical to clinical evidence. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110289. [PMID: 33631251 DOI: 10.1016/j.pnpbp.2021.110289] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/25/2021] [Accepted: 02/16/2021] [Indexed: 12/21/2022]
Abstract
Anhedonia is one of the core symptoms of major depressive disorder (MDD), which is often inadequately treated by traditional antidepressants. The modern framework of anhedonia extends the definition from impaired consummatory pleasure or interest in rewards to a broad spectrum of deficits that impact functions such as reward anticipation, approach motivation, effort expenditure, reward valuation, expectation, and reward-cue association learning. Substantial preclinical and clinical research has explored the neural basis of reward deficits in the context of depression, and has implicated mesocorticolimbic reward circuitry comprising the nucleus accumbens, ventral pallidum, ventral tegmental area, amygdala, hippocampus, anterior cingulate, insula, orbitofrontal cortex, and other prefrontal cortex regions. Dopamine modulates several reward facets including anticipation, motivation, effort, and learning. As well, serotonin, norepinephrine, opioids, glutamate, Gamma aminobutyric acid (GABA), and acetylcholine are also involved in anhedonia, and medications targeting these systems may also potentially normalize reward processing in depression. Unfortunately, whereas reward anticipation and reward outcome are extensively explored by both preclinical and clinical studies, translational gaps remain in reward motivation, effort, valuation, and learning, where clinical neuroimaging studies are in the early stages. This review aims to synthesize the neurobiological mechanisms underlying anhedonia in MDD uncovered by preclinical and clinical research. The translational difficulties in studying the neural basis of reward are also discussed.
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Affiliation(s)
- Shijing Wang
- Arthur Sommer Rotenberg Suicide and Depression Studies Program, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Francesco Leri
- Department of Psychology, University of Guelph, Ontario, Canada
| | - Sakina J Rizvi
- Arthur Sommer Rotenberg Suicide and Depression Studies Program, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
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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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Soto PL. Single‐case experimental designs for behavioral neuroscience. J Exp Anal Behav 2020; 114:447-467. [DOI: 10.1002/jeab.633] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/29/2020] [Accepted: 10/04/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Paul L. Soto
- Department of Psychology Louisiana State University
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11
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Schneider NY, Chaudy S, Epstein AL, Viollet C, Benani A, Pénicaud L, Grosmaître X, Datiche F, Gascuel J. Centrifugal projections to the main olfactory bulb revealed by transsynaptic retrograde tracing in mice. J Comp Neurol 2020; 528:1805-1819. [PMID: 31872441 DOI: 10.1002/cne.24846] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 11/26/2019] [Accepted: 11/29/2019] [Indexed: 12/14/2022]
Abstract
A wide range of evidence indicates that olfactory perception is strongly involved in food intake. However, the polysynaptic circuitry linking the brain areas involved in feeding behavior to the olfactory regions is not well known. The aim of this article was to examine such circuits. Thus, we described, using hodological tools such as transsynaptic viruses (PRV152) transported in a retrograde manner, the long-distance indirect projections (two to three synapses) onto the main olfactory bulb (MOB). The ß-subunit of the cholera toxin which is a monosynaptic retrograde tracer was used as a control to be able to differentiate between direct and indirect projections. Our tracing experiments showed that the arcuate nucleus of the hypothalamus, as a major site for regulation of food intake, sends only very indirect projections onto the MOB. Indirect projections to MOB also originate from the solitary nucleus which is involved in energy homeostasis. Other indirect projections have been evidenced in areas of the reward circuit such as VTA and accumbens nucleus. In contrast, direct projections to the MOB arise from melanin-concentrating hormone and orexin neurons in the lateral hypothalamus. Functional significances of these projections are discussed in relation to the role of food odors in feeding and reward-related behavior.
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Affiliation(s)
- Nanette Y Schneider
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, AgroSup Dijon, Université de Bourgogne Franche-Comté, F21000, Dijon, France
| | - Sylvie Chaudy
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, AgroSup Dijon, Université de Bourgogne Franche-Comté, F21000, Dijon, France
| | - Alberto L Epstein
- UMR 1179 INSERM-UVSQ-End-icap, Université de Versailles-Saint Quentin en Yvelines, Versailles, France
| | - Cécile Viollet
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, "Synaptic plasticity and Neuronal Circuits", F-75014, Paris, France
| | - Alexandre Benani
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, AgroSup Dijon, Université de Bourgogne Franche-Comté, F21000, Dijon, France
| | - Luc Pénicaud
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, AgroSup Dijon, Université de Bourgogne Franche-Comté, F21000, Dijon, France
| | - Xavier Grosmaître
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, AgroSup Dijon, Université de Bourgogne Franche-Comté, F21000, Dijon, France
| | - Frédérique Datiche
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, AgroSup Dijon, Université de Bourgogne Franche-Comté, F21000, Dijon, France
| | - Jean Gascuel
- Centre des Sciences du Goût et de l'Alimentation (CSGA), CNRS, INRAE, AgroSup Dijon, Université de Bourgogne Franche-Comté, F21000, Dijon, France
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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: 36] [Impact Index Per Article: 6.0] [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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13
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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: 37] [Impact Index Per Article: 6.2] [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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14
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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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15
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Corre J, van Zessen R, Loureiro M, Patriarchi T, Tian L, Pascoli V, Lüscher C. Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement. eLife 2018; 7:39945. [PMID: 30373717 PMCID: PMC6207421 DOI: 10.7554/elife.39945] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 10/17/2018] [Indexed: 12/21/2022] Open
Abstract
The dopamine (DA) hypothesis posits the increase of mesolimbic dopamine levels as a defining commonality of addictive drugs, initially causing reinforcement, eventually leading to compulsive consumption. While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we monitor genetically encoded DA and calcium indicators as well as cFos in mice to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.
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Affiliation(s)
- Julie Corre
- Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland
| | - Ruud van Zessen
- Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland
| | - Michaël Loureiro
- Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland
| | - Tommaso Patriarchi
- School of Medicine, Department of Biochemistry and Molecular Medicine, University of California Davis, California, United States
| | - Lin Tian
- School of Medicine, Department of Biochemistry and Molecular Medicine, University of California Davis, California, United States
| | - Vincent Pascoli
- Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland
| | - Christian Lüscher
- Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland.,Service of Neurology, University of Geneva Hospital, Geneva, Switzerland
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16
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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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17
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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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18
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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: 27] [Impact Index Per Article: 3.9] [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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19
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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: 45] [Impact Index Per Article: 6.4] [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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20
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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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21
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Coimbra B, Soares-Cunha C, Borges S, Vasconcelos NAP, Sousa N, Rodrigues AJ. Impairments in laterodorsal tegmentum to VTA projections underlie glucocorticoid-triggered reward deficits. eLife 2017; 6:e25843. [PMID: 28837419 PMCID: PMC5576484 DOI: 10.7554/elife.25843] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 07/26/2017] [Indexed: 01/15/2023] Open
Abstract
Ventral tegmental area (VTA) activity is critical for reward/reinforcement and is tightly modulated by the laterodorsal tegmentum (LDT). In utero exposure to glucocorticoids (iuGC) triggers prominent motivation deficits but nothing is known about the impact of this exposure in the LDT-VTA circuit. We show that iuGC-rats have long-lasting changes in cholinergic markers in the LDT, together with a decrease in LDT basal neuronal activity. Interestingly, upon LDT stimulation, iuGC animals present a decrease in the magnitude of excitation and an increase in VTA inhibition, as a result of a shift in the type of cells that respond to the stimulus. In agreement with LDT-VTA dysfunction, we show that iuGC animals present motivational deficits that are rescued by selective optogenetic activation of this pathway. Importantly, we also show that LDT-VTA optogenetic stimulation is reinforcing, and that iuGC animals are more susceptible to the reinforcing properties of LDT-VTA stimulation.
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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
| | - Carina Soares-Cunha
- Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B’s–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Sónia Borges
- Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B’s–PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Nivaldo AP Vasconcelos
- 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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22
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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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23
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Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior. Sci Rep 2017; 7:900. [PMID: 28420875 PMCID: PMC5429859 DOI: 10.1038/s41598-017-01088-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 03/23/2017] [Indexed: 11/30/2022] Open
Abstract
Dysfunction of cholinergic signaling in the brain has long been believed to be associated with depressive disorders. However, the functional impact of habenular cholinergic signaling on the specified depressive behaviors is not well understood. Here, we demonstrated that the expression levels of cholinergic signaling genes (CHAT, VACHT, CHT, CHRNA3, CHRNB3 and CHRNB4) were down-regulated in a chronic restraint stress (CRS) rat model of depression, in which rats display depression-like behaviors such as anhedonia and mood despair. Moreover, knockdown of CHAT in the rat habenula was sufficient to evoke anhedonia-like behavior. The anhedonia-like behavior induced by CHAT knockdown was not reversed by chronic administration of the selective serotonin reuptake inhibitor fluoxetine. To determine whether habenular cholinergic signaling is associated with regulation of dopamine neurons in the ventral tegmental area (VTA) and serotonin neurons in the dorsal raphe nucleus (DRN), we used CHAT::cre transgenic mice expressing the Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Pharmacogenetic activation of habenular cholinergic neurons induces the excitation of dopamine neurons in the VTA and reduces the immunoreactivity of 5-hydroxytryptamine (5-HT) in the DRN. Habenular cholinergic gene down-regulation was recapitulated in the postmortem habenula of suicide victims diagnosed with major depressive disorder (MDD).
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24
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Lambert MØ, Ipsen TH, Kohlmeier KA. Acute cocaine exposure elicits rises in calcium in arousal-related laterodorsal tegmental neurons. Pharmacol Res Perspect 2016; 5:e00282. [PMID: 28596834 PMCID: PMC5461641 DOI: 10.1002/prp2.282] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 10/25/2016] [Indexed: 12/17/2022] Open
Abstract
Cocaine has strong reinforcing properties, which underlie its high addiction potential. Reinforcement of use of addictive drugs is associated with rises in dopamine (DA) in mesoaccumbal circuitry. Excitatory afferent input to mesoaccumbal circuitry sources from the laterodorsal tegmental nucleus (LDT). Chronic, systemic cocaine exposure has been shown to have cellular effects on LDT cells, but acute actions of local application have never been demonstrated. Using calcium imaging, we show that acute application of cocaine to mouse brain slices induces calcium spiking in cells of the LDT. Spiking was attenuated by tetrodotoxin (TTX) and low calcium solutions, and abolished by prior exhaustion of intracellular calcium stores. Further, DA receptor antagonists reduced these transients, whereas DA induced rises with similar spiking kinetics. Amphetamine, which also results in elevated levels of synaptic DA, but via a different pharmacological action than cocaine, induced calcium spiking with similar profiles. Although large differences in spiking were not noted in an animal model associated with a heightened proclivity of acquiring addiction‐related behavior, the prenatal nicotine exposed mouse (PNE), subtle differences in cocaine's effect on calcium spiking were noted, indicative of a reduction in action of cocaine in the LDT associated with exposure to nicotine during gestation. When taken together, our data indicate that acute actions of cocaine do include effects on LDT cells. Considering the role of intracellular calcium in cellular excitability, and of the LDT in addiction circuitry, our data suggest that cocaine effects in this nucleus may contribute to the high addiction potential of this drug.
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Affiliation(s)
- Mads Ødum Lambert
- Department of Drug Design and Pharmacology Faculty of Health Sciences Universitetsparken 2 University of Copenhagen Copenhagen 2100 Denmark
| | - Theis Højland Ipsen
- Department of Drug Design and Pharmacology Faculty of Health Sciences Universitetsparken 2 University of Copenhagen Copenhagen 2100 Denmark
| | - Kristi Anne Kohlmeier
- Department of Drug Design and Pharmacology Faculty of Health Sciences Universitetsparken 2 University of Copenhagen Copenhagen 2100 Denmark
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Steidl S, Wang H, Ordonez M, Zhang S, Morales M. Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward. Eur J Neurosci 2016; 45:559-571. [PMID: 27740714 DOI: 10.1111/ejn.13436] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 09/29/2016] [Accepted: 10/07/2016] [Indexed: 01/22/2023]
Abstract
Converging evidence shows that ventral tegmental area (VTA) dopamine neurons receive laterodorsal tegmental nucleus (LDTg) cholinergic and glutamatergic inputs. To test the behavioral consequences of selectively driving the two sources of excitatory LDTg input to the VTA, channelrhodopsin-2 (ChR2) was expressed in LDTg cholinergic neurons of ChAT::Cre mice (ChAT-ChR2 mice) or in LDTg glutamatergic neurons of VGluT2::Cre mice (VGluT2-ChR2 mice). Mice were tested in a 3-chamber place preference apparatus where entry into a light-paired chamber resulted in VTA light stimulation of LDTg-cholinergic or LDTg-glutamatergic axons for the duration of a chamber stay. ChAT-ChR2 mice spent more time in the light-paired chamber and subsequently showed conditioned place preference for the light-paired chamber in the absence of light. VGluT2-ChR2 mice, entered the light-paired chamber significantly more times than a light-unpaired chamber, but remained in the light-paired chamber for short time periods and did not show a conditioned place preference. When each entry into the light-paired chamber resulted in a single train of VTA light stimulation, VGluT2-ChR2 mice entered the light-paired chamber significantly more times than the light-unpaired chamber, but spent approximately equal amounts of time in the two chambers. VTA excitation of LDTg-glutamatergic inputs may be more important for reinforcement of initial chamber entry while VTA excitation of LDTg-cholinergic inputs may be more important for the rewarding effects of chamber stays. We suggest that LDTg-cholinergic and LDTg-glutamatergic inputs to the VTA each contribute to the net rewarding effects of exciting LDTg axons in the VTA.
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Affiliation(s)
- Stephan Steidl
- Department of Psychology, Loyola University Chicago, 1032 West Sheridan Road, Chicago, IL, 60626, USA
| | - Huiling Wang
- Neuronal Networks Section, Integrative Neuroscience Research Branch, Intramural Research Program National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD, 21224, USA
| | - Marco Ordonez
- Department of Psychology, Loyola University Chicago, 1032 West Sheridan Road, Chicago, IL, 60626, USA
| | - Shiliang Zhang
- Neuronal Networks Section, Integrative Neuroscience Research Branch, Intramural Research Program National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD, 21224, USA
| | - Marisela Morales
- Neuronal Networks Section, Integrative Neuroscience Research Branch, Intramural Research Program National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD, 21224, USA
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Mena-Segovia J. Structural and functional considerations of the cholinergic brainstem. J Neural Transm (Vienna) 2016; 123:731-736. [PMID: 26945862 DOI: 10.1007/s00702-016-1530-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 02/19/2016] [Indexed: 12/24/2022]
Abstract
Cholinergic neurons of the brainstem have traditionally been associated with a role in wakefulness as part of the reticular activating system, but their function cannot be explained solely on the basis of their modulation of the brain state. Recent findings about their connectivity and functional heterogeneity suggest a wider role in behavior, where basal ganglia is at the center of their influence. This review focuses on recent findings that suggest an intrinsic functional organization of the cholinergic brainstem that is closely correlated with its connectivity with midbrain and forebrain circuits. Furthermore, recent evidence on the temporal structure of the activation of brainstem cholinergic neurons reveals fundamental aspects about the nature of cholinergic signaling. Consideration of the cholinergic brainstem complex in the context of wider brain circuits is critical to understand its contribution to normal behavior.
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Affiliation(s)
- Juan Mena-Segovia
- Center for Molecular and Behavioral Neuroscience, Aidekman Research Center, Rutgers University, Newark, NJ, 07102, USA.
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27
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Oliva I, Wanat MJ. Ventral Tegmental Area Afferents and Drug-Dependent Behaviors. Front Psychiatry 2016; 7:30. [PMID: 27014097 PMCID: PMC4780106 DOI: 10.3389/fpsyt.2016.00030] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/23/2016] [Indexed: 01/10/2023] Open
Abstract
Drug-related behaviors in both humans and rodents are commonly thought to arise from aberrant learning processes. Preclinical studies demonstrate that the acquisition and expression of many drug-dependent behaviors involves the ventral tegmental area (VTA), a midbrain structure comprised of dopamine, GABA, and glutamate neurons. Drug experience alters the excitatory and inhibitory synaptic input onto VTA dopamine neurons, suggesting a critical role for VTA afferents in mediating the effects of drugs. In this review, we present evidence implicating the VTA in drug-related behaviors, highlight the diversity of neuronal populations in the VTA, and discuss the behavioral effects of selectively manipulating VTA afferents. Future experiments are needed to determine which VTA afferents and what neuronal populations in the VTA mediate specific drug-dependent behaviors. Further studies are also necessary for identifying the afferent-specific synaptic alterations onto dopamine and non-dopamine neurons in the VTA following drug administration. The identification of neural circuits and adaptations involved with drug-dependent behaviors can highlight potential neural targets for pharmacological and deep brain stimulation interventions to treat substance abuse disorders.
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Affiliation(s)
- Idaira Oliva
- Department of Biology, Neurosciences Institute, University of Texas at San Antonio , San Antonio, TX , USA
| | - Matthew J Wanat
- Department of Biology, Neurosciences Institute, University of Texas at San Antonio , San Antonio, TX , USA
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Morello F, Partanen J. Diversity and development of local inhibitory and excitatory neurons associated with dopaminergic nuclei. FEBS Lett 2015; 589:3693-701. [PMID: 26453835 DOI: 10.1016/j.febslet.2015.10.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 09/28/2015] [Accepted: 10/01/2015] [Indexed: 12/18/2022]
Abstract
For regulation of voluntary movement and motivation the midbrain dopaminergic system receives input from a variety of brain regions. Often this input is mediated by local non-dopaminergic neurons within or closely associated with the dopaminergic nuclei. In addition to the dopaminergic neurons, some of these non-dopaminergic neurons also send functionally important output from the ventral midbrain to forebrain targets. The aim of this review is to introduce subtypes of GABAergic and glutamatergic neurons, which are located in the dopaminergic nuclei or the adjacent brainstem and are important for the regulation of the dopaminergic pathways. In addition, we discuss recent studies beginning to reveal mechanisms for their development, which may hold the key to understanding the diversity of these neurons.
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Affiliation(s)
- Francesca Morello
- Department of Biosciences, Division of Genetics, P.O. Box 56, Viikinkaari 9, 00014 University of Helsinki, Helsinki, Finland
| | - Juha Partanen
- Department of Biosciences, Division of Genetics, P.O. Box 56, Viikinkaari 9, 00014 University of Helsinki, Helsinki, Finland.
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Psychophysical inference of frequency-following fidelity in the neural substrate for brain stimulation reward. Behav Brain Res 2015; 292:327-41. [PMID: 26057357 DOI: 10.1016/j.bbr.2015.06.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 06/01/2015] [Accepted: 06/03/2015] [Indexed: 01/16/2023]
Abstract
The rewarding effect of electrical brain stimulation has been studied extensively for 60 years, yet the identity of the underlying neural circuitry remains unknown. Previous experiments have characterized the directly stimulated ("first-stage") neurons implicated in self-stimulation of the medial forebrain bundle. Their properties are consistent with those of fine, myelinated axons, at least some of which project rostro-caudally. These properties do not match those of dopaminergic neurons. The present psychophysical experiment estimates an additional first-stage characteristic: maximum firing frequency. We test a frequency-following model that maps the experimenter-set pulse frequency into the frequency of firing induced in the directly stimulated neurons. As pulse frequency is increased, firing frequency initially increases at the same rate, then becomes probabilistic, and finally levels off. The frequency-following function is based on the counter model which holds that the rewarding effect of a pulse train is determined by the aggregate spike rate triggered in first-stage neurons during a given interval. In 7 self-stimulating rats, we measured current- vs. pulse-frequency trade-off functions. The trade-off data were well described by the frequency-following model, and its upper asymptote was approached at a median value of 360 Hz (IQR = 46 Hz). This value implies a highly excitable, non-dopaminergic population of first-stage neurons. Incorporating the frequency-following function and parameters in Shizgal's 3-dimensional reward-mountain model improves its accuracy and predictive power.
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