Exploring the in vivo subthreshold membrane activity of phasic firing in midbrain dopamine neurons

  • Dopamine is a key neurotransmitter that serves several essential functions in daily behaviors such as locomotion, motivation, stimulus coding, and learning. Disrupted dopamine circuits can result in altered functions of these behaviors which can lead to motor and psychiatric symptoms and diseases. In the central nervous system, dopamine is primarily released by dopamine neurons located in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) within the midbrain, where they signal behaviorally-relevant information to downstream structures by altering their firing patterns. Their “pacemaker” firing maintains baseline dopamine levels at projection sites, whereas phasic “burst” firing transiently elevates dopamine concentrations. Firing activity of dopamine neurons projecting to different brain regions controls the activation of distinct dopamine pathways and circuits. Therefore, characterization of how distinct firing patterns are generated in dopamine neuron populations will be necessary to further advance our understanding of dopamine circuits that encode environmental information and facilitate a behavior. However, there is currently a large gap in the knowledge of biophysical mechanisms of phasic firing in dopamine neurons, as spontaneous burst firing is only observed in the intact brain, where access to intrinsic neuronal activity remains a challenge. So far, a series of highly-influential studies published in the 1980s by Grace and Bunney is the only available source of information on the intrinsic activity of midbrain dopamine neurons in vivo, in which sharp electrodes were used to penetrate dopamine neurons to record their intracellular activity. A novel approach is thus needed to fill in the gap. In vivo whole-cell patch-clamp method is a tool that enables access to a neuron’s intrinsic activity and subthreshold membrane potential dynamics in the intact brain. It has been used to record from neurons in superficial brain regions such as the cortex and hippocampus, and more recently in deeper regions such as the amygdala and brainstem, but has not yet been performed on midbrain dopamine neurons. Thus, the deep brain in vivo patch-clamp recording method was established in the lab in an attempt to investigate the subthreshold membrane potential dynamics of tonic and phasic firing in dopamine neurons in vivo. The use of this method allowed the first in-depth examination of burst firing and its subthreshold membrane potential activity of in vivo midbrain dopamine neurons, which illuminated that firing activity and subthreshold membrane activity of dopamine neurons are very closely related. Furthermore, systematic characterization of subthreshold membrane patterns revealed that tonic and phasic firing patterns of in vivo dopamine neurons can be classified based on three distinct subthreshold membrane signatures: 1) tonic firing, characterized by stable, non-fluctuating subthreshold membrane potentials; 2) rebound bursting, characterized by prominent hyperpolarizations that initiate bursting; and 3) plateau bursting, characterized by transient, depolarized plateaus on which bursting terminates. The results thus demonstrated that different types of phasic firing are driven by distinct patterns of subthreshold membrane activity, which may potentially signal distinct types of information. Taken together, the deep brain in vivo patch-clamp technique can be used for the investigation of firing mechanisms of dopamine neurons in the intact brain and will help address open questions in the dopamine field, particularly regarding the biophysical mechanisms of burst firing in dopamine neurons that control behavior.
  • Dopamin ist ein essenzieller Neurotransmitter, der mehrere wesentliche Funktionen bei alltäglichen Verhaltensweisen wie Fortbewegung, Motivation, Reizkodierung und Lernen erfüllt. Störungen im dopaminergen System können zu veränderten Funktionen dieser Verhaltensweisen führen, was zu motorischen und psychiatrischen Symptomen und Krankheiten führen kann. Im zentralen Nervensystem wird der Großteil des Dopamins von dopaminergen Neuronen freigesetzt, die sich in der Substantia nigra pars compacta (SNc) und im ventralen tegmentum (VTA) im Mittelhirn befinden, wo sie verhaltensrelevante Informationen an nachgeschaltete Strukturen überitteln, indem sie ihre Feuerungsmuster verändern. Ihre "Schrittmacher"-Aktivität hält die Dopamin-Konzentration an den Projektionsstellen auf einem konstant niedrigen Niveau aufrecht, während phasisches "Burst"-Feuern die Dopamin-Konzentration vorübergehend ansteigen lässt...

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar
Metadaten
Author:Kanako OtomoORCiDGND
URN:urn:nbn:de:hebis:30:3-613882
DOI:https://doi.org/10.21248/gups.61388
Place of publication:Frankfurt am Main
Referee:Manfred KösslORCiD, Gilles Laurent, Amparo Acker-PalmerORCiDGND, Henner HollertORCiDGND
Advisor:Manfred Kössl, Hiroshi Ito, Jochen Roeper
Document Type:Doctoral Thesis
Language:English
Date of Publication (online):2021/06/28
Year of first Publication:2021
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Granting Institution:Johann Wolfgang Goethe-Universität
Date of final exam:2021/06/24
Release Date:2021/09/21
Page Number:135
HeBIS-PPN:485679523
Institutes:Biowissenschaften
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Sammlung Biologie / Biologische Hochschulschriften (Goethe-Universität)
Licence (German):License LogoDeutsches Urheberrecht