Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose neurodevelopmental symptoms include impaired executive function, attention, and spatial learning and could be due to perturbed mesolimbic dopaminergic circuitry. However, these circuits have never been directly assayed in vivo. We employed the genetically encoded optical dopamine sensor dLight1 to monitor dopaminergic neurotransmission in the ventral striatum of NF1 mice during motivated behavior. Additionally, we developed novel systemic AAV vectors to facilitate morphological reconstruction of dopaminergic populations in cleared tissue. We found that NF1 mice exhibit reduced spontaneous dopaminergic neurotransmission that was associated with excitation/inhibition imbalance in the ventral tegmental area and abnormal neuronal morphology. NF1 mice also had more robust dopaminergic and behavioral responses to salient visual stimuli, which were independent of learning, and rescued by optogenetic inhibition of non-dopaminergic neurons in the VTA. Overall, these studies provide a first in vivo characterization of dopaminergic circuit function in the context of NF1 and reveal novel pathophysiological mechanisms.

Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times

“…DA neurons originating in the VTA are known to be modulated by aversive stimuli, and have been implicated in fear conditioning and extinction ( El-Ghundi et al, 2001 ; Young et al, 1993 ; Inoue et al, 2000 ; Nader and LeDoux, 1999 ; Guarraci and Kapp, 1999 ; Holtzman-Assif et al, 2010 ; Delgado et al, 2008 ; Luo et al, 2018 ; Salinas-Hernández et al, 2018 ; Zweifel et al, 2011 ; Pezze and Feldon, 2004 ; Mueller et al, 2010 ; Pignatelli et al, 2017 ; Nasehi et al, 2016 ; Pezze et al, 2003 ; Budygin et al, 2012 ; Robinson et al, 2019 ; Lammel et al, 2011 ; Jo et al, 2018 ; Lutas et al, 2019 ; Fadok et al, 2009 ; Groessl et al, 2018 ; Bouchet et al, 2018 ; Wenzel et al, 2018 ; Wang and Tsien, 2011 ; Mileykovskiy and Morales, 2011 ). However, it was unclear if and how neural correlates of fear extinction are topographically organized within the VTA.…”

“…Although most work examining neural correlates of behavior in VTA DA neurons has focused on reward-based tasks, several studies have recorded VTA DA neuron activity during aversive associations ( Robinson et al, 2019 ; Lutas et al, 2019 ; Wang and Tsien, 2011 ; Mileykovskiy and Morales, 2011 ). In particular, VTA DA neurons were shown to represent RPE-like signals during fear extinction, in that they display elevated activity when the shock is omitted at the offset of the cue, signaling better-than-expected outcome ( Salinas-Hernández et al, 2018 ; Badrinarayan et al, 2012 ; Jo et al, 2018 ).…”

Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times

“…DA neurons originating in the VTA are known to be modulated by aversive stimuli, and have been implicated in fear conditioning and extinction (El-Ghundi, O'Dowd, and George 2001;Young, Joseph, and Gray 1993;Inoue et al 2000;Nader and LeDoux 1999;Guarraci and Kapp 1999;Holtzman-Assif, Laurent, and Westbrook 2010;Delgado et al 2008;Luo et al 2018;Salinas-Hernández et al 2018;Zweifel et al 2011;Pezze and Feldon 2004;Mueller, Bravo-Rivera, and Quirk 2010;Pignatelli et al 2017;Nasehi et al 2016;Pezze, Bast, and Feldon 2003;Budygin et al 2012;Robinson et al 2019;Lammel et al 2011;Jo, Heymann, and Zweifel 2018;Lutas et al 2019;Fadok, Dickerson, and Palmiter 2009;Groessl et al 2018;Bouchet et al 2018;Wenzel et al 2018;Wang and Tsien 2011;Mileykovskiy and Morales 2011) . However, it was unclear if and how neural correlates of fear extinction are topographically organized within the VTA.…”

“…Although most work examining neural correlates of behavior in VTA DA neurons has focused on reward-based tasks, several studies have recorded VTA DA neuron activity during aversive associations (Robinson et al 2019;Lutas et al 2019;Wang and Tsien 2011;Mileykovskiy and Morales 2011) . In particular, VTA DA neurons were shown to represent RPE-like signals during fear extinction, in that they display elevated activity when the shock is omitted at the offset of the cue, signaling better-than-expected outcome (Salinas-Hernández et al 2018;Badrinarayan et al 2012;Jo, Heymann, and Zweifel 2018) .…”

GPCR-Based Dopamine Sensors—A Detailed Guide to Inform Sensor Choice for In Vivo Imaging

“…In Table 1 you will find a summary of currently available DA biosensors as well as their main properties, which are further detailed in Section 5 . DA biosensors have already generated key findings in the basic understanding of reward behavior [ 101 , 102 , 103 , 104 , 105 , 106 , 107 ], thirst regulation [ 108 ], feeding behavior [ 109 ], addiction [ 38 , 110 , 111 ], aversive learning [ 112 ], depressive-like behavior [ 98 ], sleep-wake cycle [ 113 ] or to dissect neuromodulator mechanisms in disease models [ 114 , 115 ] using a variety of in vivo imaging modalities shown in Figure 1 . DA biosensors can also be used to understand DA release dynamics in vitro or ex vivo [ 58 , 59 , 60 , 61 ], as shown for example in Reference [ 116 ] where dLight1 was used to understand the metabolic demands and bioenergetic roles of the mitochondria in governing phasic DA release.…”