Midbrain | EPFL Graph Search

The midbrain or mesencephalon is the rostral-most portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek mesos, "middle", and enkephalos, "brain". Anatomy The midbrain is the shortest segment of the brainstem, measuring at less than 2cm in length. It is situated mostly in the posterior cranial fossa, with its superior part extending above the tentorial notch. Structure The principal regions of the midbrain are the tectum, the cerebral aqueduct, tegmentum, and the cerebral peduncles. Rostrally the midbrain adjoins the diencephalon (thalamus, hypothalamus, etc.), while caudally it adjoins the hindbrain (pons, medulla and cerebellum). In the rostral direc

The dopaminergic VTA - basal amygdala projection contributes to signal aversive state in fear memory

Wei Tang

Dopamine released from midbrain neurons is an important neuromodulatory signal during associative learning in many forebrain circuits. One model of associative learning is auditory cued fear learning, during which an innocuous sensory percept like a tone (called conditioned stimulus, CS), acquires an aversive meaning after pairing with an aversive event, like a mild footshock (called unconditioned stimulus, US). The amygdala plays an important role in fear learning in mammals. Nevertheless, our knowledge of the synaptic- or neuromodulatory input(s) which carry information about the US to the amygdala is still limited. Here, I have investigated the hypothesis that dopamine, released from midbrain dopaminergic neurons in the ventral tegmental area (VTA) of mice, might signal aversive sensory events to the amygdala during fear learning. Using viral anterograde tracing approaches in transgenic mice expressing Cre-recombinase under the control of the dopamine transporter promoter (DAT-Cre), we found a dopaminergic projection from VTA to the basal amygdala (BA) and to the central amygdala (CeA). In addition, retrograde tracing approaches showed that tyrosine hydroxylase positive (TH+) dopamine neurons targeting these two areas might be differentially distributed in the VTA. To investigate a role of these projections during fear learning, we silenced the electrical activity of VTA dopamine neurons, or else their projection fibers to the BA or the CeA, by using Cre-dependent expression of a light-driven proton pump Archaerhodopsin (Arch). Silencing VTA neurons specifically during the footshock presentation (US) led to a moderate reduction of fear memory tested one day following the initial US - CS pairing. Silencing the dopaminergic fibers bilaterally in the BA (but not in the CeA) during footshock presentation had a somewhat larger effect on fear memory retrieval, and similarly reduced contextual fear memory. Furthermore, we made recordings of the spiking activity of DAT+ - as well as of non-identified VTA neurons in-vivo in behaving mice using optrodes. We found that about half of all units strongly respond to footshock stimulation (US), and show increasing responses to tones (CS) during the US - CS pairing. To investigate the possible cellular functions of dopamine in the BA during fear learning, we performed in-vitro recordings of genetically identified parvalbumin (PV)-positive interneurons and BA principal neurons that project to the CeA. This showed that bath application of dopamine or of a D1- receptor agonist enhances the evoked firing rate of CeA projectors in the BA. Finally, bath application of dopamine reduces afferent excitatory inputs onto PV-positive interneurons in the BA and in the LA. Taken together, by using complementary optogenetic, electrophysiological and anatomical approaches, this PhD thesis suggests that VTA dopamine neurons facilitate associative learning in the BA by providing a neuromodulatory signal to the BA during the time of the footshock. Furthermore, the VTA might also provide dopamine to the amygdala during fear memory retrieval. Thus, this work contributes to an understanding of the functional role of the dopaminergic VTA to BA projection in auditory-cued fear learning.

EPFL2018

Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function

Patrick Aebischer, Julien Dusonchet, Sylvain Eric Lengacher, Bernard Schneider

Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinsons disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1 induces mitochondrial biogenesis and increases basal respiration. Over time, we observe an increasing proportion of the oxygen consumed by neurons which are dedicated to adenosine triphosphate production. In parallel to enhanced oxidative phosphorylation, PGC-1 progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1 induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1 prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1 is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1 overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by -synuclein overexpression. Overall, we find that lasting overexpression of PGC-1 leads to major alterations in the metabolic activity of neuronal cells which dramatically impair dopaminergic function in vivo. These results highlight the central role of PGC-1 in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1 activity.

Oxford University Press2012

Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells

Gioele La Manno, Jesper Ryge

Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.

2016