Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease

Sci Rep. 2016 Oct 20:6:35203. doi: 10.1038/srep35203.


The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Dopamine / metabolism*
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Gastrin-Releasing Peptide / genetics*
  • Gastrin-Releasing Peptide / metabolism
  • Gene Expression Regulation
  • Glutamic Acid / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Optogenetics
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Pars Compacta / metabolism*
  • Pars Compacta / pathology
  • Synaptic Transmission
  • TRPV Cation Channels / genetics*
  • TRPV Cation Channels / metabolism
  • Ventral Tegmental Area / metabolism*
  • Ventral Tegmental Area / pathology
  • gamma-Aminobutyric Acid / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurod6 protein, mouse
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Gastrin-Releasing Peptide
  • Dopamine