Guillaume M. Fortin

Mindfulness-based therapy: a comprehensive meta-analysis.

BACKGROUND Mindfulness-based therapy (MBT) has become a popular form of intervention. However, the existing reviews report inconsistent findings. OBJECTIVE To clarify these inconsistencies in the literature, we conducted a comprehensive effect-size analysis to evaluate the efficacy of MBT. DATA SOURCES A systematic review of studies published in journals or in dissertations in PubMED or PsycINFO from the first available date until May 10, 2013. REVIEW METHODS A total of 209 studies (n=12,145) were included. RESULTS Effect-size estimates suggested that MBT is moderately effective in pre-post comparisons (n=72; Hedges g=.55), in comparisons with waitlist controls (n=67; Hedges g=.53), and when compared with other active treatments (n=68; Hedges g=.33), including other psychological treatments (n=35; Hedges g=.22). MBT did not differ from traditional CBT or behavioral therapies (n=9; Hedges g=-.07) or pharmacological treatments (n=3; Hedges g=.13). CONCLUSION MBT is an effective treatment for a variety of psychological problems, and is especially effective for reducing anxiety, depression, and stress.

Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice

The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2f/f;DAT-Cre) to address the functional significance of the glutamate–DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.

Glutamate Corelease Promotes Growth and Survival of Midbrain Dopamine Neurons

Recent studies have proposed that glutamate corelease by mesostriatal dopamine (DA) neurons regulates behavioral activation by psychostimulants. How and when glutamate release by DA neurons might play this role remains unclear. Considering evidence for early expression of the type 2 vesicular glutamate transporter in mesencephalic DA neurons, we hypothesized that this cophenotype is particularly important during development. Using a conditional gene knock-out approach to selectively disrupt the Vglut2 gene in mouse DA neurons, we obtained in vitro and in vivo evidence for reduced growth and survival of mesencephalic DA neurons, associated with a decrease in the density of DA innervation in the nucleus accumbens, reduced activity-dependent DA release, and impaired motor behavior. These findings provide strong evidence for a functional role of the glutamatergic cophenotype in the development of mesencephalic DA neurons, opening new perspectives into the pathophysiology of neurodegenerative disorders involving the mesostriatal DA system.

Ultrastructural characterization of the mesostriatal dopamine innervation in mice, including two mouse lines of conditional VGLUT2 knockout in dopamine neurons

Despite the increasing use of genetically modified mice to investigate the dopamine (DA) system, little is known about the ultrastructural features of the striatal DA innervation in the mouse. This issue is particularly relevant in view of recent evidence for expression of the vesicular glutamate transporter 2 (VGLUT2) by a subset of mesencephalic DA neurons in mouse as well as rat. We used immuno‐electron microscopy to characterize tyrosine hydroxylase (TH)‐labeled terminals in the core and shell of nucleus accumbens and the neostriatum of two mouse lines in which the Vglut2 gene was selectively disrupted in DA neurons (cKO), their control littermates, and C57BL/6/J wild‐type mice, aged P15 or adult. The three regions were also examined in cKO mice and their controls of both ages after dual TH–VGLUT2 immunolabeling. Irrespective of the region, age and genotype, the TH‐immunoreactive varicosities appeared similar in size, vesicular content, percentage with mitochondria, and exceedingly low frequency of synaptic membrane specialization. No dually labeled axon terminals were found at either age in control or in cKO mice. Unless TH and VGLUT2 are segregated in different axon terminals of the same neurons, these results favor the view that the glutamatergic cophenotype of mesencephalic DA neurons is more important during the early development of these neurons than for the establishment of their scarce synaptic connectivity. They also suggest that, in mouse even more than rat, the mesostriatal DA system operates mainly through non‐targeted release of DA, diffuse transmission and the maintenance of an ambient DA level.

Evaluation of D1 and D2 dopamine receptor segregation in the developing striatum using BAC transgenic mice.

The striatum is predominantly composed of medium spiny neurons (MSNs) that send their axons along two parallel pathways known as the direct and indirect pathways. MSNs from the direct pathway express high levels of D1 dopamine receptors, while MSNs from the indirect pathway express high levels of D2 dopamine receptors. There has been much debate over the extent of colocalization of these two major dopamine receptors in MSNs of adult animals. In addition, the ontogeny of the segregation process has never been investigated. In this paper, we crossed bacterial artificial chromosome drd1a-tdTomato and drd2-GFP reporter transgenic mice to characterize these models and estimate D1-D2 co-expression in the developing striatum as well as in striatal primary cultures. We show that segregation is already extensive at E18 and that the degree of co-expression further decreases at P0 and P14. Finally, we also demonstrate that cultured MSNs maintain their very high degree of D1-D2 reporter protein segregation, thus validating them as a relevant in vitro model.

A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

Midbrain dopaminergic (DAergic) neurons are a heterogeneous cell group, composed of functionally distinct cell populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, the midbrain population of DAergic neurons is sparse, constituting only 20 000–30 000 neurons in mice, and development of novel tools to identify these cells is warranted. Here, a bacterial artificial chromosome mouse line [Dat1‐enhanced green fluorescent protein (eGFP)] from the Gene Expression Nervous System Atlas (GENSAT) that expresses eGFP under control of the dopamine transporter (DAT) promoter was characterized. Confocal microscopy analysis of brain sections showed strong eGFP signal reporter in midbrain regions and striatal terminals that co‐localized with the DAergic markers DAT and tyrosine hydroxylase (TH). Thorough quantification of co‐localization of the eGFP reporter signal with DAT and TH in the ventral midbrain showed that a vast majority of eGFP‐expressing neurons are DAergic. Importantly, expression profiles also revealed DAergic heterogeneity when comparing substantia nigra and ventral tegmental area. Dat1‐eGFP mice showed neither change in synaptosomal DA uptake nor altered levels of DAT and TH in both striatum and midbrain. No behavioural difference between Dat1‐eGFP and wild‐type was found, suggesting that the strain is not aberrant. Finally, cell populations highly enriched in DAergic neurons can be obtained from postnatal mice by fluorescence‐activated cell sorting and the sorted neurons can be cultured in vitro. The current investigation demonstrates that eGFP expression in this mouse line is selective for DAergic neurons, suggesting that the Dat1‐eGFP mouse strain constitutes a promising tool for delineating new aspects of DA biology.

Axonal Segregation and Role of the Vesicular Glutamate Transporter VGLUT3 in Serotonin Neurons

A subset of monoamine neurons releases glutamate as a cotransmitter due to presence of the vesicular glutamate transporters VGLUT2 or VGLUT3. In addition to mediating vesicular loading of glutamate, it has been proposed that VGLUT3 enhances serotonin (5-HT) vesicular loading by the vesicular monoamine transporter (VMAT2) in 5-HT neurons. In dopamine (DA) neurons, glutamate appears to be released from specialized subsets of terminals and it may play a developmental role, promoting neuronal growth and survival. The hypothesis of a similar developmental role and axonal localization of glutamate co-release in 5-HT neurons has not been directly examined. Using postnatal mouse raphe neurons in culture, we first observed that in contrast to 5-HT itself, other phenotypic markers of 5-HT axon terminals such as the 5-HT reuptake transporter (SERT) show a more restricted localization in the axonal arborization. Interestingly, only a subset of SERT- and 5-HT-positive axonal varicosities expressed VGLUT3, with SERT and VGLUT3 being mostly segregated. Using VGLUT3 knockout mice, we found that deletion of this transporter leads to reduced survival of 5-HT neurons in vitro and also decreased the density of 5-HT-immunoreactivity in terminals in the dorsal striatum and dorsal part of the hippocampus in the intact brain. Our results demonstrate that raphe 5-HT neurons express SERT and VGLUT3 mainly in segregated axon terminals and that VGLUT3 regulates the vulnerability of these neurons and the neurochemical identity of their axonal domain, offering new perspectives on the functional connectivity of a cell population involved in anxiety disorders and depression.

Psychosocial well-being construct in people with severe mental disorders enrolled in supported employment programs.

The main purpose of this prospective study is to validate the construct of psychosocial well-being (PSWB) for people with severe mental disorders enrolled in Supported Employment (SE) programs. This paper also aims to assess the impact of job acquisition on PSWB after obtaining competitive employment. A two-phase study approach was used and 231 individuals with severe mental disorders enrolled in SE programs who took part in both phases. The shortened versions of the Psychological Well-Being Scale (Keyes et al. in J Personal Soc Psychol, 82(6):1007–1022, 2002; Ryff and Keyes in J Personal Soc Psychol 69(4):719–727, 1995) and the Social Well-Being Scale (Keyes in Soc Psychol Q 61(2):121–140, 1998) were used. The PSWB’s multidimensionality construct was confirmed. The results of repeated measure ANOVA analyses revealed that job acquisition, as well as, being involved in a work-seeking process increase the PSWB of people with severe mental disorders. Employment specialists might find clinical utility in using this validated tool for assessing PSWB in their clients with severe mental disorders. In a recovery oriented approach to psychiatric services and SE programs, clinicians and employment specialists should continue to encourage their clients in their work integration process even though they may not all obtain competitive employment quickly.

Segregation of dopamine and glutamate release sites in dopamine neuron axons: regulation by striatal target cells

Dopamine (DA) is a key regulator of circuits controlling movement and motivation. A. subset of midbrain DA neurons has been shown to express the vesicular glutamate transporter (VGLUT)2, underlying their capacity for glutamate release. Glutamate release is found mainly by DA neurons of the ventral tegmental area (VTA) and can be detected at terminals contacting ventral, but not dorsal, striatal neurons, suggesting the possibility that target‐derived signals regulate the neurotransmitter phenotype of DA neurons. Whether glutamate can be released from the same terminals that release DA or from a special subset of axon terminals is unclear. Here, we provide in vitro and in vivo data supporting the hypothesis that DA and glutamate‐releasing terminals in mice are mostly segregated and that striatal neurons regulate the cophenotype of midbrain DA neurons and the segregation of release sites. Our work unveils a fundamental feature of dual neurotransmission and plasticity of the DA system.—Fortin, G. M., Ducrot, C., Giguère, N., Kouwenhoven, W. M., Bourque, M.‐J., Pacelli, C., Varaschin, R. K., Brill, M., Singh, S., Wiseman, P. W., Trudeau, L.‐E. Segregation of dopamine and glutamate release sites in dopamine neuron axons: regulation by striatal target cells. FASEB J. 33, 400–417 (2019). www.fasebj.org

Does personality influence job acquisition and tenure in people with severe mental illness enrolled in supported employment programs

Abstract Background: When employment difficulties in people with severe mental illness (SMI) occur, it could be partly linked to issues not specific to SMI, such as personality traits or problems. Despite the fact that personality has a marked influence on almost every aspect of work behavior, it has scarcely been investigated in the context of employment for people with SMI. Aims: We aimed to evaluate if personality was more predictive than clinical variables of different competitive work outcomes, namely acquisition of competitive employment, delay to acquisition and job tenure. Method: A sample of 82 people with a SMI enrolled in supported employment programs (SEP) was recruited and asked to complete various questionnaires and interviews. Statistical analyses included logistic regressions and survival analyses (Cox regressions). Results: Prior employment, personality problems and negative symptoms are significantly related to acquisition of a competitive employment and to delay to acquisition whereas the conscientiousness personality trait was predictive of job tenure. Conclusion: Our results point out the relevance of personality traits and problems as predictors of work outcomes in people with SMI registered in SEP. Future studies should recruit larger samples and also investigate these links with other factors related to work outcomes.