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Brain Sciences
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Advanced Research on Dopaminergic Neurons and Their Role in Depression
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Advanced Research on Dopaminergic Neurons and Their Role in Depression

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Systems Neuroscience".

Deadline for manuscript submissions: closed (8 June 2022) | Viewed by 22942

Special Issue Editor

Dr. Màté D. Döbrössy

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Guest Editor
Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Hospital Freiburg, Freiburg, Germany
Interests: neuromodulation; Deep Brain Stimulation; depression; experimental models of depression; neurocircuitry of depression

Special Issue Information

Dear Colleauges,

What is the rationale for studying dopamine’s role in Major Depressive Disorder?

Major Depressive Disorder (depression) is a multifactorial, biologically and symptomatically heterogeneous condition. Amongst the numerous—and potentially equally valid—proposals concerning its aetiology (e.g., inflammation, genetics, stress-related mechanisms, etc.), one of the longest-standing ideas is the “monoamine hypothesis” stating that one or more dysfunctional monoamine systems are key contributors in the development of this psychiatric disorder. Historically, most of the research focus has been on the role of serotonin and noradrenalin. Although this might not be “The” biological explanation for depression, a dysfunctional monoamine system, dopamine system in particular, is likely to contribute to the emergence of the two “sine qua non” symptoms associated with depression: on one hand, depressed mood and reduced motivation/perseverance and on the other, anhedonia and loss of interest in what were previously pleasurable activities. There is growing interest in dopamine’s role in clinical depression, especially, in the way it works as a modulator of the brain’s reward systems. Furthermore, there is pre-clinical evidence that A10 dopaminergic neurons projecting from the midbrain ventral tegmental area to the nucleus accumbens and dorsolateral prefrontal cortical areas over several routes are associated with motivation, exploration, appetitive learning, reward-driven behaviours, and a depressive-like phenotype in experimental models of depression. The reward systems might also be implicated in aversive stimuli, a recent notion which needs to be further explored.

This Special Issue of Brain Sciences aims to bring together some of the current ideas on the function or dysfunction of dopamine and dopaminergic transmission in depression, by examining the most recent evidence from advanced clinical and experimental research. It will gather insights from well-acclaimed experts in the field towards answering the ultimate question: what is the true role of dopamine in Major Depression?

Dr. Màté D. Döbrössy
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • dopamine
  • major depressive disorder
  • biological substrates of depression
  • clinical and experimental research

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Published Papers (6 papers)

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Research

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12 pages, 1121 KiB  
Communication
New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens
by Lidia Miguel Telega, Danesh Ashouri Vajari, Thomas Stieglitz, Volker A. Coenen and Máté D. Döbrössy
Brain Sci. 2022, 12(8), 1105; https://doi.org/10.3390/brainsci12081105 - 19 Aug 2022
Cited by 4 | Viewed by 3687
Abstract
New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. [...] Read more.
New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action. Full article
(This article belongs to the Special Issue Advanced Research on Dopaminergic Neurons and Their Role in Depression)
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14 pages, 691 KiB  
Article
Dopamine Function and Hypothalamic-Pituitary-Thyroid Axis Activity in Major Depressed Patients with Suicidal Behavior
by Fabrice Duval, Marie-Claude Mokrani, Vlad Danila, Alexis Erb, Felix Gonzalez Lopera and Mihaela Tomsa
Brain Sci. 2022, 12(5), 621; https://doi.org/10.3390/brainsci12050621 - 10 May 2022
Cited by 10 | Viewed by 4132
Abstract
Involvement of the dopaminergic (DA) and hypothalamic-pituitary-thyroid (HPT) systems in suicidal behavior is still poorly understood. We assessed multihormonal responses to apomorphine (APO; a short acting DA receptor agonist) and 8 AM and 11 PM protirelin (TRH) tests in 30 medication-free DSM-5 euthyroid [...] Read more.
Involvement of the dopaminergic (DA) and hypothalamic-pituitary-thyroid (HPT) systems in suicidal behavior is still poorly understood. We assessed multihormonal responses to apomorphine (APO; a short acting DA receptor agonist) and 8 AM and 11 PM protirelin (TRH) tests in 30 medication-free DSM-5 euthyroid major depressed inpatients with suicidal behavior disorder (SBD) (current, n = 14; in early remission, n = 16) and 18 healthy hospitalized control subjects (HCs). Compared to HCs, responses to APO and TRH tests were unaltered in SBDs in early remission. However, current SBDs exhibited increased APO-induced growth hormone (GH) and adrenocorticotropin (ACTH) stimulation, and reduced 11 PM thyrotropin (TSH) and ∆∆TSH values (difference between 11 PM and 8 AM TRH-TSH responses). In current SBDs, the association between high APO-GH concentrations and low ∆∆TSH values was more common in recent suicide attempters than in past suicide attempters. These preliminary results suggest that co-occurring alterations in the DA and HPT systems (i.e., DA receptor hyperresponsiveness associated with decreased hypothalamic TRH drive) may contribute to the pathophysiology of suicidal behavior. Conversely, normalization of DA and TRH functions might reflect a process of recovery from suicidality. Thus, our findings suggest that drugs targeting the DAergic and TRH systems could be relevant in suicide prevention. Full article
(This article belongs to the Special Issue Advanced Research on Dopaminergic Neurons and Their Role in Depression)
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15 pages, 677 KiB  
Article
Behavioral Phenotype in Heterozygous DAT Rats: Transgenerational Transmission of Maternal Impact and the Role of Genetic Asset
by Greta Manoni, Concetto Puzzo, Antonella Gigantesco and Walter Adriani
Brain Sci. 2022, 12(4), 469; https://doi.org/10.3390/brainsci12040469 - 31 Mar 2022
Cited by 4 | Viewed by 2465
Abstract
Dopamine transporter (DAT) is involved in dopamine (DA) reuptake in presynaptic terminals. Deletion of DAT results in a hyperdopaminergic KO-rat phenotype. To conduct our studies in heterozygous DAT rats, several pedigree lines were created, with known derivation of the allele (i.e., maternal or [...] Read more.
Dopamine transporter (DAT) is involved in dopamine (DA) reuptake in presynaptic terminals. Deletion of DAT results in a hyperdopaminergic KO-rat phenotype. To conduct our studies in heterozygous DAT rats, several pedigree lines were created, with known derivation of the allele (i.e., maternal or paternal). Our purpose was to elucidate the role of parental origin rather than maternal care, assessing if maternal maltreatments generated sequelae in female offspring. In the first experiment, female rats and their pups were observed during postnatal lactation. Control dams were WT and heterozygous ones were MAT (but K-MAT, with previous experience of early maltreatment by their KO adoptive dams). WT dams were highly attracted to their offspring (predictably, they spent a lot of time licking their pups); in contrast, K-MAT dams showed strangely comparable levels of caring for their pups and exploring the environment. Subsequently, peculiar features of the circadian cycle were found in adolescent rats with different epigenotypes (WT, MUX = offspring of MAT father, MIK = offspring of K-MAT dam). The MIK epigenotype produced locomotor hyperactivity also during resting hours, well above typical values. The MUX epigenotype, on the other hand, was less active and presented a depression-like profile. This study is unique: maltreatment was generated in a spontaneous way from a DAT-KO mother to offspring. We highlight how future studies will address separate contributions by genotype and upbringing. In conclusion, paternal-allele asset generates sequelae diametrically opposed to the inheritance of early maternal trauma. Full article
(This article belongs to the Special Issue Advanced Research on Dopaminergic Neurons and Their Role in Depression)
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Review

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16 pages, 598 KiB  
Review
In Search of Digital Dopamine: How Apps Can Motivate Depressed Patients, a Review and Conceptual Analysis
by Stephane Mouchabac, Redwan Maatoug, Ismael Conejero, Vladimir Adrien, Olivier Bonnot, Bruno Millet, Florian Ferreri and Alexis Bourla
Brain Sci. 2021, 11(11), 1454; https://doi.org/10.3390/brainsci11111454 - 1 Nov 2021
Cited by 9 | Viewed by 4918
Abstract
Introduction: Depression is highly prevalent and causes considerable suffering and disease burden despite the existence of wide-ranging treatment options. Momentary assessment is a promising tool in the management of psychiatric disorders, and particularly depression. It allows for a real-time evaluation of symptoms and [...] Read more.
Introduction: Depression is highly prevalent and causes considerable suffering and disease burden despite the existence of wide-ranging treatment options. Momentary assessment is a promising tool in the management of psychiatric disorders, and particularly depression. It allows for a real-time evaluation of symptoms and an earlier detection of relapse or treatment efficacy. Treating the motivational and hedonic aspects of depression is a key target reported in the literature, but it is time-consuming in terms of human resources. Digital Applications offer a major opportunity to indirectly regulate impaired motivational circuits through dopaminergic pathways. Objective: The main objective of this review was twofold: (1) propose a conceptual and critical review of the literature regarding the theoretical and technical principles of digital applications focused on motivation in depression, activating dopamine, and (2) suggest recommendations on the relevance of using these tools and their potential place in the treatment of depression. Material and Methods: A search for words related to “dopamine”, “depression”, “smartphone apps”, “digital phenotype” has been conducted on PubMed. Results: Ecological momentary interventions (EMIs) differ from traditional treatments by providing relevant, useful intervention strategies in the context of people’s daily lives. EMIs triggered by ecological momentary assessment (EMA) are called “Smart-EMI”. Smart-EMIs can mimic the “dopamine reward system” if the intervention is tailored for motivation or hedonic enhancement, and it has been shown that a simple reward (such as a digital badge) can increase motivation. Discussion: The various studies presented support the potential interest of digital health in effectively motivating depressed patients to adopt therapeutic activation behaviors. Finding effective ways to integrate EMIs with human-provided therapeutic support may ultimately yield the most efficient and effective intervention method. This approach could be a helpful tool to increase adherence and motivation. Conclusion: Smartphone apps can motivate depressed patients by enhancing dopamine, offering the opportunity to enhance motivation and behavioral changes, although longer term studies are still needed. Full article
(This article belongs to the Special Issue Advanced Research on Dopaminergic Neurons and Their Role in Depression)
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Other

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14 pages, 2206 KiB  
Perspective
Dopamine and Beyond: Implications of Psychophysical Studies of Intracranial Self-Stimulation for the Treatment of Depression
by Vasilios Pallikaras and Peter Shizgal
Brain Sci. 2022, 12(8), 1052; https://doi.org/10.3390/brainsci12081052 - 8 Aug 2022
Cited by 4 | Viewed by 3066
Abstract
Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been [...] Read more.
Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been achieved through the use of deep brain stimulation of the medial forebrain bundle (MFB). The beneficial effect of such stimulation appears strong, safe, and enduring. The proposed neural substrate for this promising clinical finding includes midbrain dopamine neurons and a subset of their cortical afferents. Here, we aim to broaden the discussion of the candidate circuitry by exploring potential implications of a new “convergence” model of brain reward circuitry in rodents. We chart the evolution of the new model from its predecessors, which held that midbrain dopamine neurons constituted an obligatory stage of the final common path for reward seeking. In contrast, the new model includes a directly activated, non-dopaminergic pathway whose output ultimately converges with that of the dopaminergic neurons. On the basis of the new model and the relative ineffectiveness of dopamine agonists in the treatment of depression, we ask whether non-dopaminergic circuitry may contribute to the clinical efficacy of deep brain stimulation of the MFB. Full article
(This article belongs to the Special Issue Advanced Research on Dopaminergic Neurons and Their Role in Depression)
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18 pages, 2607 KiB  
Perspective
“The Heart Asks Pleasure First”—Conceptualizing Psychiatric Diseases as MAINTENANCE Network Dysfunctions through Insights from slMFB DBS in Depression and Obsessive–Compulsive Disorder
by Volker A. Coenen, Thomas E. Schlaepfer, Bastian E. A. Sajonz, Peter C. Reinacher, Máté D. Döbrössy and Marco Reisert
Brain Sci. 2022, 12(4), 438; https://doi.org/10.3390/brainsci12040438 - 25 Mar 2022
Cited by 6 | Viewed by 3333
Abstract
More than a decade ago, deep brain stimulation (DBS) of the superolateral medial forebrain bundle (slMFB), as part of the greater MFB system, had been proposed as a putative yet experimental treatment strategy for therapy refractory depression (TRD) and later for obsessive–compulsive disorders [...] Read more.
More than a decade ago, deep brain stimulation (DBS) of the superolateral medial forebrain bundle (slMFB), as part of the greater MFB system, had been proposed as a putative yet experimental treatment strategy for therapy refractory depression (TRD) and later for obsessive–compulsive disorders (OCD). Antidepressant and anti-OCD efficacy have been shown in open case series and smaller trials and were independently replicated. The MFB is anato-physiologically confluent with the SEEKING system promoting euphoric drive, reward anticipation and reward; functions realized through the mesocorticolimbic dopaminergic system. Growing clinical experience concerning surgical and stimulation aspects from a larger number of patients shows an MFB functionality beyond SEEKING and now re-informs the scientific rationale concerning the MFB’s (patho-) physiology. In this white paper, we combine observations from more than 75 cases of slMFB DBS. We integrate these observations with a selected literature review to provide a new neuroethological view on the MFB. We here formulate a re-interpretation of the MFB as the main structure of an integrated SEEKING/MAINTENANCE circuitry, allowing for individual homeostasis and well-being through emotional arousal, basic and higher affect valence, bodily reactions, motor programing, vigor and flexible behavior, as the basis for the antidepressant and anti-OCD efficacy. Full article
(This article belongs to the Special Issue Advanced Research on Dopaminergic Neurons and Their Role in Depression)
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