title: Activation of Pedunculopontine Glutamate Neurons Is Reinforcing.
abstract: Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders.
  
  
  
  Uncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement.
authors.affiliation: Department of Neurosciences and.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Yoo
authors.affiliation: Department of Neurosciences and.
authors.forename: Vivien
authors.initials: V
authors.lastname: Zell
authors.affiliation: Department of Neurosciences and.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Neurosciences and.
authors.forename: Cindy
authors.initials: C
authors.lastname: Punta
authors.affiliation: Department of Neurosciences and.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Ramajayam
authors.affiliation: Department of Neurosciences and.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Neurosciences and.
authors.forename: Lauren
authors.initials: L
authors.lastname: Faget
authors.affiliation: Department of Biological Sciences, University of California, San Diego, La Jolla, California 92093.
authors.forename: Varoth
authors.initials: V
authors.lastname: Lilascharoen
authors.affiliation: Department of Biological Sciences, University of California, San Diego, La Jolla, California 92093.
authors.forename: Byung Kook
authors.initials: BK
authors.lastname: Lim
authors.affiliation: Department of Neurosciences and thnasko@ucsd.edu.
authors.forename: Thomas S
authors.identifier: 0000-0001-6176-8513
authors.initials: TS
authors.lastname: Hnasko
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002755:Choice Behavior; D059290:Dopaminergic Neurons / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D062308:Optogenetics; D045042:Pedunculopontine Tegmental Nucleus / Q000166:cytology / Q000502:physiology*; D010775:Photic Stimulation; D012201:Reward; D012653:Self Stimulation; D017557:Ventral Tegmental Area / Q000166:cytology / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid
keywords: dopamine; glutamate; optogenetics; pedunculopontine; reward; ventral tegmental area