Cre-driven optogenetics in the heterogeneous genetic panorama of the VTA

Pupe, Stéfano; Wallén-Mackenzie, Åsa

doi:10.1016/j.tins.2015.04.005

Cited by 47 publications

(46 citation statements)

References 90 publications

(132 reference statements)

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“…Questions have been raised regarding the use of TH-Cre mouse lines to selectively target midbrain dopamine neurons, due to the potential for ‘ectopic' expression of TH transcript and Cre expression in neurons that contain little or no TH protein5460. Such questions raise important issues about what markers constitute a specific class of VTA neuron, whether such markers are stable across development and in the adult, and the use of Cre-expressing mouse lines to target-specific cell types6162. For these reasons we validated our findings using multiple Cre lines.…”

Section: Discussionmentioning

confidence: 99%

Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement

et al. 2016

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In addition to dopamine neurons, the ventral tegmental area (VTA) contains GABA-, glutamate- and co-releasing neurons, and recent reports suggest a complex role for the glutamate neurons in behavioural reinforcement. We report that optogenetic stimulation of VTA glutamate neurons or terminals serves as a positive reinforcer on operant behavioural assays. Mice display marked preference for brief over sustained VTA glutamate neuron stimulation resulting in behavioural responses that are notably distinct from dopamine neuron stimulation and resistant to dopamine receptor antagonists. Whole-cell recordings reveal EPSCs following stimulation of VTA glutamate terminals in the nucleus accumbens or local VTA collaterals; but reveal both excitatory and monosynaptic inhibitory currents in the ventral pallidum and lateral habenula, though the net effects on postsynaptic firing in each region are consistent with the observed rewarding behavioural effects. These data indicate that VTA glutamate neurons co-release GABA in a projection-target-dependent manner and that their transient activation drives positive reinforcement.

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Section: Discussionmentioning

confidence: 99%

Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement

et al. 2016

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“…First, the use of DAT-Cre mice, especially the controls ( Slc17a6 +/flox ; Slc6a3 +/IRESCre ), served as a complement for the experiment where TH-Cre mice were used, and vice versa. This is because the TH-Cre line expresses Cre in some non-DA neurons (Lammel et al, 2015; Lindenberg, 2004; Nordenankar et al, 2015; Pupe and Wallen-Mackenzie, 2015), and some TH-expressing VTA neurons, particularly those located in the medial VTA, do not express DAT (Lammel et al, 2015; Viereckel et al, 2016). Second, a 50-Hz train employed in the present study was adequate for examining fast activation of striatal neurons despite the reports that 50-Hz optogenetic stimulation does not trigger reliable depolarization at each pulse in vitro (Tsai et al, 2009; Witten et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation

et al. 2017

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Summary Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. While it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.

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“…Thus, when glutamate and DA are multiplexed together—as they are in some mesoaccumbal projections (Zhang et al, 2015)—DA may act to modulate glutamatergic signaling, counter glutamatergic signaling, or might even behave differently depending on the postsynaptic cell (e.g., targeting of D1 receptor neurons or D2 receptor neurons). With this in mind, it is clear that novel technologies and intersectional genetic strategies will be necessary in order to decipher the unique contributions of each component of multiplexed signals (Pupe et al, 2015). …”

Section: Multiplexed Transmission: Future Directions and Consideratiomentioning

confidence: 99%

Multiplexed neurochemical signaling by neurons of the ventral tegmental area

Barker

Root

Zhang

et al. 2016

Journal of Chemical Neuroanatomy

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The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in ‘multiplexed’ neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression.

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Cre-driven optogenetics in the heterogeneous genetic panorama of the VTA

Cited by 47 publications

References 90 publications

Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement

Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement

Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation

Multiplexed neurochemical signaling by neurons of the ventral tegmental area

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