Neuroscience
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The knowledge that diverse populations of dopaminergic neurons within the ventral tegmental area (VTA) can be distinguished in terms of their molecular, electrophysiological and functional properties, as well as their differential projections to cortical and subcortical regions has significance for key brain functions, such as the regulation of motivation, working memory and sensorimotor control. Almost without exception, this understanding has evolved from landmark studies performed in the male sex. However, converging evidence from both clinical and pre-clinical studies illustrates that the structure and functioning of the VTA dopaminergic systems are intrinsically different in males and females. ⋯ Here, also, there is male/female diversity not only during adulthood, but also in early life when neurobiological programing by stress or glucocorticoid exposure differentially impacts dopaminergic developmental trajectories in male and female brains. This may have enduring consequences for individual resilience or susceptibility to pathophysiological change induced by stressors in later life, with potential translational significance for sex bias commonly found in disorders involving dysfunction of the mesocorticolimbic dopaminergic systems. These findings highlight the urgent need for a better understanding of the sexual dimorphism in the VTA if we are to improve strategies for the prevention and treatment of debilitating conditions which differentially affect men and women in their prevalence and nature, including schizophrenia, attention/deficit hyperactivity disorder, autism spectrum disorders, anxiety, depression and addiction.
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The ventral tegmental area (VTA) is a brain region processing salient sensory and emotional information, controlling motivated behaviors, natural or drug-related reward, reward-related learning, mood, and participating in their associated psychopathologies. Mostly studied for its dopamine neurons, the VTA also includes functionally important GABA and glutamate cell populations. Behavioral evidence supports the presence of functional differences between the anterior VTA (aVTA) and the posterior VTA (pVTA), which is the topic of this review. ⋯ This region, partly located within the pVTA, is an inhibitory control center for dopamine activity. It controls VTA and substantia nigra dopamine cells, thus exerting a major influence on basal ganglia functions. This review highlights the need for a more comprehensive analysis of VTA heterogeneity.
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Projection systems arising from the ventral tegmental area (VTA) and the substantia nigra (SN) have a critical role in a broad range of functions, as well as in the etiology, symptoms and treatment of neurological and psychiatric diseases. Mostly studied for its dopamine neurons, the ventral tegmentum is in fact heterogeneous at cellular and functional levels. ⋯ Recent progress also highlights the need for molecular markers of functional subpopulations within the ventral tegmentum, for deeper developmental knowledge of this region, and for a single cell level of connectomic. It also raises the question of inter-individual, sex, strain and species heterogeneity, and conversely the question of data generalization in a context of human pathology models, which warrant comparative studies and translational effort.
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Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine. These Gi/o-coupled inhibitory receptors play a major part in shaping dopamine transmission. ⋯ Alterations in the expression and activity of autoreceptors are thought to contribute to Parkinson's disease as well as schizophrenia, drug addiction and attention-deficit hyperactivity disorder (ADHD), which emphasizes the importance of D2-autoreceptors in regulating the dopamine system. This review will summarize the cellular actions of dopamine autoreceptors and discuss recent advances that have furthered our understanding of the mechanisms by which D2-receptors control dopamine transmission.
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Review
The heterogeneity of ventral tegmental area neurons: Projection functions in a mood-related context.
The ventral tegmental area (VTA) in the brain's reward circuitry is composed of a heterogeneous population of dopamine, GABA, and glutamate neurons that play important roles in mediating mood-related functions including depression. These neurons project to different brain regions, including the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the amygdala. The functional understanding of these projection pathways has been improved since the extensive use of advanced techniques such as viral-mediated gene transfer, cell-type-specific neurophysiology and circuit-probing optogenetics. In this article, we will discuss the recent progress in understanding these VTA projection-specific functions, focusing on mood-related disorders.