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Article ; Online: The mesopontine tegmentum in reward and aversion: From cellular heterogeneity to behaviour.

Bastos-Gonçalves, Ricardo / Coimbra, Bárbara / Rodrigues, Ana João

2024 Volume 162, Page(s) 105702

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 ... ...

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.
Language	English
Publishing date	2024-05-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	282464-4
ISSN	1873-7528 ; 0149-7634
ISSN (online)	1873-7528
ISSN	0149-7634
DOI	10.1016/j.neubiorev.2024.105702
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Article ; Online: Nucleus accumbens neurons dynamically respond to appetitive and aversive associative learning.

Deseyve, Catarina / Domingues, Ana Verónica / Carvalho, Tawan T A / Armada, Gisela / Correia, Raquel / Vieitas-Gaspar, Natacha / Wezik, Marcelina / Pinto, Luísa / Sousa, Nuno / Coimbra, Bárbara / Rodrigues, Ana João / Soares-Cunha, Carina

Journal of neurochemistry

2024 Volume 168, Issue 3, Page(s) 312–327

Abstract: To survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by ... ...

Abstract	To survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by GABAergic medium spiny neurons (MSNs), that express either dopamine receptor D1 or D2. Recent studies showed that both populations can drive reward and aversion, however, the activity of these neurons during appetitive and aversive Pavlovian conditioning remains to be determined. Here, we investigated the relevance of D1- and D2-neurons in associative learning, by measuring calcium transients with fiber photometry during appetitive and aversive Pavlovian tasks in mice. Sucrose was used as a positive valence unconditioned stimulus (US) and foot shock was used as a negative valence US. We show that during appetitive Pavlovian conditioning, D1- and D2-neurons exhibit a general increase in activity in response to the conditioned stimuli (CS). Interestingly, D1- and D2-neurons present distinct changes in activity after sucrose consumption that dynamically evolve throughout learning. During the aversive Pavlovian conditioning, D1- and D2-neurons present an increase in the activity in response to the CS and to the US (shock). Our data support a model in which D1- and D2-neurons are concurrently activated during appetitive and aversive conditioning.
MeSH term(s)	Animals ; Mice ; Nucleus Accumbens/metabolism ; Receptors, Dopamine D1/metabolism ; Conditioning, Classical ; Neurons/metabolism ; Avoidance Learning/physiology ; Sucrose/pharmacology
Chemical Substances	Receptors, Dopamine D1 ; Sucrose (57-50-1)
Language	English
Publishing date	2024-02-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.16063
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Article ; Online: Negative associations between maternal prenatal hair cortisol and child socioemotional problems.

Mustonen, Paula / Kortesluoma, Susanna / Scheinin, Noora M / Perasto, Laura / Kataja, Eeva-Leena / Tervahartiala, Katja / Tuulari, Jetro J / Coimbra, Bárbara / Carter, Alice S / Rodrigues, Ana João / Sousa, Nuno / Paavonen, E Juulia / Korja, Riikka / Karlsson, Hasse / Karlsson, Linnea

Psychoneuroendocrinology

2024 Volume 162, Page(s) 106955

Abstract: Maternal prenatal distress can participate in the programming of offspring development, in which exposure to altered maternal long-term cortisol levels as measured by hair cortisol concentrations (HCC) may contribute. Yet, studies investigating whether ... ...

Abstract	Maternal prenatal distress can participate in the programming of offspring development, in which exposure to altered maternal long-term cortisol levels as measured by hair cortisol concentrations (HCC) may contribute. Yet, studies investigating whether and how maternal prenatal HCC associates with problems in child socioemotional development are scarce. Furthermore, questions remain regarding the timing and potential sex-specificity of fetal exposure to altered cortisol levels and whether there are interactions with maternal prenatal distress, such as depressive symptoms. The subjects were drawn from those FinnBrain Birth Cohort families that had maternal reports of child socioemotional problems (the Brief Infant-Toddler Social and Emotional Assessment [BITSEA] at 2 years and/or the Strengths and Difficulties Questionnaire [SDQ] at 5 years) as follows: HCC1 population: maternal mid-pregnancy HCC measured at gestational week 24 with 5 cm segments to depict cortisol levels from the previous five months (n = 321); and HCC2 population: end-of-pregnancy HCC measured 1-3 days after childbirth (5 cm segment; n = 121). Stepwise regression models were utilized in the main analyses and a sensitivity analysis was performed to detect potential biases. Negative associations were observed between maternal HCC2 and child BITSEA Total Problems at 2 years but not with SDQ Total difficulties at 5 years, and neither problem score was associated with HCC1. In descriptive analyses, HCC2 was negatively associated with Internalizing problems at 2 years and SDQ Emotional problems at 5 years. A negative association was observed among 5-year-old girls between maternal HCC1 and SDQ Total Difficulties and the subscales of Conduct and Hyperactivity/inattentive problems. When interactions were also considered, inverse associations between HCC2 and BITSEA Internalizing and Dysregulation Problems were observed in subjects with elevated prenatal depressive symptoms. It was somewhat surprising that only negative associations were observed between maternal HCC and child socioemotional problems. However, there are previous observations of elevated end-of-pregnancy cortisol levels associating with better developmental outcomes. The magnitudes of the observed associations were, as expected, mainly modest. Future studies with a focus on the individual changes of maternal cortisol levels throughout pregnancy as well as studies assessing both maternal and child HPA axis functioning together with child socioemotional development are indicated.
MeSH term(s)	Female ; Infant ; Pregnancy ; Humans ; Child, Preschool ; Hydrocortisone/analysis ; Hypothalamo-Hypophyseal System/chemistry ; Prenatal Exposure Delayed Effects ; Pituitary-Adrenal System/chemistry ; Hair/chemistry ; Obstetric Labor Complications
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article
ZDB-ID	197636-9
ISSN	1873-3360 ; 0306-4530
ISSN (online)	1873-3360
ISSN	0306-4530
DOI	10.1016/j.psyneuen.2023.106955
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Article ; Online: Involvement of nucleus accumbens D2-medium spiny neurons projecting to the ventral pallidum in anxiety-like behaviour.

Correia, Raquel / Coimbra, Bárbara / Domingues, Ana Verónica / Wezik, Marcelina / Vieitas-Gaspar, Natacha / Gaspar, Rita / Sousa, Nuno / Pinto, Luísa / Rodrigues, Ana João / Soares-Cunha, Carina

Journal of psychiatry & neuroscience : JPN

2023 Volume 48, Issue 4, Page(s) E267–E284

Abstract: Background: The nucleus accumbens (NAcc) is a crucial brain region for emotionally relevant behaviours. The NAcc is mainly composed of medium spiny neurons (MSNs) expressing either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). The D1-MSNs project to ... ...

Abstract	Background: The nucleus accumbens (NAcc) is a crucial brain region for emotionally relevant behaviours. The NAcc is mainly composed of medium spiny neurons (MSNs) expressing either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). The D1-MSNs project to the ventral tegmental area (VTA) and the ventral pallidum (VP), whereas the D2-MSNs project only to the VP. The D1- and D2-MSNs have been associated with depression-like behaviours, but their contribution to anxiety remains to be determined. Methods: We used optogenetic tools to selectively manipulate D1-MSN projections from the NAcc core to the VP or VTA and D2-MSN projections to the VP during validated anxiety-producing behavioural procedures in naive mice. In addition, we assessed the effects of optical stimulation on neuronal activity using in vivo electrophysiologic recordings in anesthetized animals. Results: Optogenetic activation of D1-MSN projections to the VTA or VP did not trigger anxiety-like behaviour. However, optical activation of D2-MSN projections to the VP significantly increased anxiety-like behaviour. This phenotype was associated with a decrease in the neuronal activity of putative GABAergic neurons in the VP. Importantly, pretreating D2-MSN-VP animals with the γ-aminobutyric acid modulator diazepam prevented the optically triggered anxiety-like behaviour. Limitations: The exclusive use of males in the behavioural tests limits broader interpretation of the findings. Although we used optogenetic conditions that trigger quasi-physiologic changes, there are caveats associated with the artificial manipulation of neuronal activity. Conclusion: The D2-MSN-VP projections contributed to the development of anxiety-like behaviour, through modulation of GABAergic activity in the VP.
MeSH term(s)	Male ; Animals ; Mice ; Nucleus Accumbens ; Medium Spiny Neurons ; Basal Forebrain ; Anxiety ; Anxiety Disorders
Language	English
Publishing date	2023-07-12
Publishing country	Canada
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1077443-9
ISSN	1488-2434 ; 1180-4882
ISSN (online)	1488-2434
ISSN	1180-4882
DOI	10.1503/jpn.220111
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Article ; Online: Laterodorsal tegmentum-ventral tegmental area projections encode positive reinforcement signals.

Coimbra, Bárbara / Domingues, Ana Verónica / Soares-Cunha, Carina / Correia, Raquel / Pinto, Luísa / Sousa, Nuno / Rodrigues, Ana João

Journal of neuroscience research

2021 Volume 99, Issue 11, Page(s) 3084–3100

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, ...

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.
MeSH term(s)	Animals ; Dopaminergic Neurons/physiology ; Male ; Nucleus Accumbens ; Rats ; Reward ; Tegmentum Mesencephali ; Ventral Tegmental Area/physiology
Language	English
Publishing date	2021-08-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.24931
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Article: The correlation between serum vascular endothelial growth factor (VEGF) and tumor VEGF receptor 3 in colorectal cancer.

Goulart, André / Ferreira, Carla / Rodrigues, Ana / Coimbra, Barbara / Sousa, Nuno / Leão, Pedro

Annals of surgical treatment and research

2019 Volume 97, Issue 1, Page(s) 15–20

Abstract: Purpose: Despite plasma biomarkers offering a number of advantages over tissue-based markers, the relationship between serum vascular endothelial growth factor (VEGF) and VEGF receptor (VEGF-R) tumor expression in colorectal cancer (CRC) is still ... ...

Abstract	Purpose: Despite plasma biomarkers offering a number of advantages over tissue-based markers, the relationship between serum vascular endothelial growth factor (VEGF) and VEGF receptor (VEGF-R) tumor expression in colorectal cancer (CRC) is still unclear. This study was designed to establish the relationship between the concentration of serum VEGF and tumor VEGF-R expression in patients with CRC. Methods: A prospective study of consecutive patients undergoing elective colorectal surgery during 1 year. Preoperative VEGF was determined by enzyme-linked immunosorbent assay and VEGF-R3 by immunochemistry. Results: The initial sample included 134 patients with CRC diagnosis. Results showed significant association of serum values of VEGF with VEGF-R3 expression (P < 0.001), even in the presence of confounders (sex, age, body mass index, tumor location, and surgical approach). The estimated effect size was high (η Conclusion: Serum VEGF has a significant correlation with tumoral VEGF-R3 expression in CRC.
Language	English
Publishing date	2019-06-26
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	3012234-X
ISSN	2288-6796 ; 2288-6575
ISSN (online)	2288-6796
ISSN	2288-6575
DOI	10.4174/astr.2019.97.1.15
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Article ; Online: A novel isolation method for spontaneously released extracellular vesicles from brain tissue and its implications for stress-driven brain pathology.

Gomes, Patrícia A / Bodo, Cristian / Nogueras-Ortiz, Carlos / Samiotaki, Martina / Chen, Minghao / Soares-Cunha, Carina / Silva, Joana M / Coimbra, Bárbara / Stamatakis, George / Santos, Liliana / Panayotou, George / Tzouanou, Foteini / Waites, Clarissa L / Gatsogiannis, Christos / Sousa, Nuno / Kapogiannis, Dimitrios / Costa-Silva, Bruno / Sotiropoulos, Ioannis

Cell communication and signaling : CCS

2023 Volume 21, Issue 1, Page(s) 35

Abstract: Background: Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human ...

Abstract	Background: Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human biospecimens, especially in complex disorders in which pathological and specimen heterogeneity, as well as diverse individual clinical profile, often complicate the development of precision therapeutic schemes and patient-tailored treatments. Thus, the collection and characterization of physiologically relevant sEVs are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV fractions with intracellular vesicles. Methods: Based on multiscale analytical platforms such as cryo-EM, label-free proteomics, advanced flow cytometry, and ExoView analyses, we compared and characterized the EV fraction isolated with this novel method with a classical digestion-based EV isolation procedure. Moreover, EV biogenesis was pharmacologically manipulated with either GW4869 or picrotoxin to assess the validity of the spontaneous-release method, while the injection of labelled-EVs into the mouse brain further supported the integrity of the isolated vesicles. Results: We hereby present an efficient purification method that captures a sEV-enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated, as well as under animals' exposure to chronic stress, a clinically relevant precipitant of brain pathologies, such as depression and Alzheimer's disease. Our findings show that the released method monitors the drug-evoked inhibition or enhancement of sEVs secretion while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress-driven brain pathology. Conclusions: Overall, the spontaneous release method of sEV yield may contribute to the characterization and biomarker profile of physiologically relevant brain-derived sEVs in brain function and pathology. Video Abstract.
MeSH term(s)	Humans ; Animals ; Mice ; Extracellular Vesicles ; Exosomes ; Brain ; Biomarkers ; Alzheimer Disease
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-02-13
Publishing country	England
Document type	Video-Audio Media ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-023-01045-z
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Article ; Online: Prenatal dexamethasone exposure alters effort decision making and triggers nucleus accumbens and anterior cingulate cortex functional changes in male rats.

Domingues, Ana Verónica / Coimbra, Bárbara / Correia, Raquel / Deseyve, Catarina / Vieitas-Gaspar, Natacha / Floresco, Stan B / Sousa, Nuno / Soares-Cunha, Carina / Rodrigues, Ana João

Translational psychiatry

2022 Volume 12, Issue 1, Page(s) 338

Abstract: Daily, individuals select actions based on cost-benefit to allocate resources into goal-directed actions. Different brain regions coordinate this complex decision, including the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and ventral ... ...

Abstract	Daily, individuals select actions based on cost-benefit to allocate resources into goal-directed actions. Different brain regions coordinate this complex decision, including the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and ventral tegmental area (VTA). In utero exposure to synthetic glucocorticoids (iuGC), such as dexamethasone, triggers prominent motivation deficits but the impact of this exposure in the ACC-NAc and/or ACC-VTA circuits is unknown. Here, we show that iuGC exposure causes decreased motivation for natural rewards (food) and impaired effort-based decision-making. Importantly, reduced neuronal activation (number of c-fos
MeSH term(s)	Animals ; Decision Making/physiology ; Dexamethasone/pharmacology ; Female ; Gyrus Cinguli/physiology ; Male ; Nucleus Accumbens ; Pregnancy ; Rats ; Reward ; Ventral Tegmental Area
Chemical Substances	Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2022-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-022-02043-4
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Article: Chronic Stress Does Not Influence the Survival of Mouse Models of Glioblastoma.

Lopes, Marta / Vieira de Castro, Joana / Pojo, Marta / Gonçalves, Céline S / Martins, Eduarda P / Coimbra, Bárbara / Sotiropoulos, Ioannis / Sousa, Nuno / Rodrigues, Ana João / Costa, Bruno M

Frontiers in oncology

2022 Volume 12, Page(s) 856210

Abstract: The existence of a clear association between stress and cancer is still a matter of debate. Recent studies suggest that chronic stress is associated with some cancer types and may influence tumor initiation and patient prognosis, but its role in brain ... ...

Abstract	The existence of a clear association between stress and cancer is still a matter of debate. Recent studies suggest that chronic stress is associated with some cancer types and may influence tumor initiation and patient prognosis, but its role in brain tumors is not known. Glioblastoma (GBM) is a highly malignant primary brain cancer, for which effective treatments do not exist. Understanding how chronic stress, or its effector hormones glucocorticoids (GCs), may modulate GBM aggressiveness is of great importance. To address this, we used both syngeneic and xenograft
Language	English
Publishing date	2022-03-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.856210
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Article: The Duration of Stress Determines Sex Specificities in the Vulnerability to Depression and in the Morphologic Remodeling of Neurons and Microglia.

Gaspar, Rita / Soares-Cunha, Carina / Domingues, Ana Verónica / Coimbra, Bárbara / Baptista, Filipa I / Pinto, Luísa / Ambrósio, António F / Rodrigues, Ana João / Gomes, Catarina A

Frontiers in behavioral neuroscience

2022 Volume 16, Page(s) 834821

Abstract: Stress exposure has been shown to induce a variety of molecular and functional alterations associated with anxiety and depression. Some studies suggest that microglia, the immune cells of the brain, play a significant role in determining neuronal and ... ...

Abstract	Stress exposure has been shown to induce a variety of molecular and functional alterations associated with anxiety and depression. Some studies suggest that microglia, the immune cells of the brain, play a significant role in determining neuronal and behavioral responses to chronic stress and also contribute to the development of stress-related psychopathologies. However, little is known about the impact of the duration of stress exposure upon microglia and neurons morphology, particularly considering sex differences. This issue deserves particular investigation, considering that the process of morphologic remodeling of neurons and microglia is usually accompanied by functional changes with behavioral expression. Here, we examine the effects of short and long unpredictable chronic mild stress (uCMS) protocols on behavior, evaluating in parallel microglia and neurons morphology in the dorsal hippocampus (dHIP) and in the
Language	English
Publishing date	2022-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2022.834821
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