Development and function of the midbrain dopamine system: what we know and what we need to

Abstract

The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson’s disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study.

Maternal Separation Impairs Cocaine-Induced Behavioural Sensitization in Adolescent Mice

“…In this system, DA neurons project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which is an important substrate for rewarding experiences together with other brain areas including the amygdala, the hippocampus and the prefrontal cortex [13,14]. Interestingly, several transcriptional factors regulate the homeostasis of the DA system including the orphan nuclear receptor-related factor 1 (Nurr1) and the paired-like homeobox 3 gene (Pitx3) [15,16]. Nurr1 activates the transcription of the DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2), and tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of DA [15].…”

From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models

“…Expression appears to be primarily limited to the soma, as there was not clear evidence of terminal staining in the striatum (Figure 2). Proteins enriched in nigral DA neurons typically have important roles in DA cell survival (Bissonette and Roesch, 2016). Thus, our findings suggest that mechanistic studies to determine how OPTN influences dopamine neuron integrity should be conducted.…”

Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson’s disease

“…A summary of the functions of genes involved in development, differentiation and maintenance of dopaminergic neurons is presented in figure 6D. Sonic hedgehog (SHH), WNT1 and FGF8 are important early genes that induce the expression of FOXA2, LMX1A, LMX1B and EN1 during the earliest stages of midbrain dopaminergic neuron development, which further drive the expression of NURR1 and PITX3 and thereby lead to expression of TH, VMAT2, DRD2, DDC, DAT and ALDH1A1 that define the 23 dopaminergic neuron phenotype [46][47][48][49][50][51][52] . Further, studies have implicated the role of genes such as RGS4, GRB10 and RSPO2 that are downstream LMX1A in midbrain dopaminergic neurogenesis and differentiation 53,54 .…”