Impairments in laterodorsal tegmentum to VTA projections underlie glucocorticoid-triggered reward deficits

Ventral tegmental area (VTA) activity is critical for reward/reinforcement and is tightly modulated by the laterodorsal tegmentum (LDT). In utero exposure to glucocorticoids (iuGC) triggers prominent motivation deficits but nothing is known about the impact of this exposure in the LDT-VTA circuit. We show that iuGC-rats have long-lasting changes in cholinergic markers in the LDT, together with a decrease in LDT basal neuronal activity. Interestingly, upon LDT stimulation, iuGC animals present a decrease in the magnitude of excitation and an increase in VTA inhibition, as a result of a shift in the type of cells that respond to the stimulus. In agreement with LDT-VTA dysfunction, we show that iuGC animals present motivational deficits that are rescued by selective optogenetic activation of this pathway. Importantly, we also show that LDT-VTA optogenetic stimulation is reinforcing, and that iuGC animals are more susceptible to the reinforcing properties of LDT-VTA stimulation.

Download Full-text

Ventral tegmental area glutamate neurons mediate the nonassociative consequences of traumatic stress

10.1101/2021.04.02.438264 ◽

2021 ◽

Author(s):

Dillon J McGovern ◽

Koy L Ecton ◽

David T Huynh ◽

Andrew R Rau ◽

Shane T Hentges ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Neuronal Activity ◽

Neuron Activity ◽

Social Avoidance ◽

Ventral Tegmental ◽

Behavioral Sequelae ◽

Physically Identical ◽

Neuron Function ◽

Stressor Controllability ◽

The Impact

Exposure to trauma is a risk factor for the development of a number of mood disorders, and may enhance vulnerability to future adverse life events. Recent data implicate ventral tegmental area (VTA) glutamate neuronal activity as functionally important for signaling aversive or threating stimuli. However, it is unknown whether VTA glutamate neurons regulate transsituational outcomes that result from stress and whether these neurons are sensitive to stressor controllability. This work established an operant mouse paradigm to examine the impact of stressor controllability on VTA glutamate neuron function and stressor outcome. Uncontrollable (inescapable) stress, but not physically identical controllable (escapable) stress, produced social avoidance in male mice. Cell-type-specific calcium recordings showed that both controllable and uncontrollable stressors increased VTA glutamate neuronal activity. Chemogenetic reduction of VTA glutamate neuron activity prevented the behavioral sequelae of uncontrollable stress. Our results provide causal evidence that mice can be used to model stressor controllability and that VTA glutamate neurons may contribute to transsituational stressor outcomes, such as social avoidance and exaggerated fear that are observed within trauma-related disorders.

Download Full-text

The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons

Molecular Psychiatry ◽

10.1038/s41380-021-01137-7 ◽

2021 ◽

Author(s):

Hongsheng Wang ◽

Wanpeng Cui ◽

Wenbing Chen ◽

Fang Liu ◽

Zhaoqi Dong ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Molecular Mechanisms ◽

Critical Role ◽

Coping With Stress ◽

Chemical Genetic ◽

Chronic Social Defeat Stress ◽

Ventral Tegmental ◽

Laterodorsal Tegmentum ◽

Specific Deletion

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

Download Full-text

Disruptions in effort-based decision-making following acute optogenetic stimulation of ventral tegmental area dopamine cells

Learning & Memory ◽

10.1101/lm.053082.120 ◽

2021 ◽

Vol 28 (4) ◽

pp. 104-108

Author(s):

Benjamin R. Fry ◽

Nathan T. Pence ◽

Andrew McLocklin ◽

Alexander W. Johnson

Keyword(s):

Decision Making ◽

Ventral Tegmental Area ◽

Optogenetic Stimulation ◽

Ventral Tegmental ◽

Stimulation Of

Download Full-text

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat

Experimental Brain Research ◽

10.1007/s00221-016-4558-z ◽

2016 ◽

Vol 234 (6) ◽

pp. 1505-1514 ◽

Cited By ~ 12

Author(s):

Ai-Ling Li ◽

Jiny E. Sibi ◽

Xiaofei Yang ◽

Jung-Chih Chiao ◽

Yuan Bo Peng

Keyword(s):

Ventral Tegmental Area ◽

Dorsal Horn ◽

Neuronal Activity ◽

Spinal Dorsal Horn ◽

Spinal Dorsal ◽

Ventral Tegmental ◽

Stimulation Of

Download Full-text

Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption

10.1101/2020.08.03.228452 ◽

2020 ◽

Author(s):

Kate Z Peters ◽

Andrew M J Young ◽

James E McCutcheon

Keyword(s):

Ventral Tegmental Area ◽

Neuronal Activity ◽

Neural Responses ◽

Internal States ◽

Licking Behaviour ◽

Psychiatric Conditions ◽

Ventral Tegmental ◽

Adaptive Behaviours ◽

External Stimuli

AbstractDisruptions in attention, salience and increased distractibility are implicated in multiple psychiatric conditions. The ventral tegmental area (VTA) is a potential site for converging information about external stimuli and internal states to be integrated and guide adaptive behaviours. Given the dual role of dopamine signals in both driving ongoing behaviours (e.g. feeding) and monitoring salient environmental stimuli, understanding the interaction between these functions is crucial. Here we investigate VTA neuronal activity during distraction from ongoing feeding. We developed a task to assess distraction exploiting self-paced licking in rats. Rats trained to lick for saccharin were given a distraction test, in which three consecutive licks within 1 second triggered a random distractor (e.g. light and tone stimulus). On each trial they were quantified as distracted or not based on the length of their pauses in licking behaviour. We expressed GCaMP6s in VTA neurons and used fibre photometry to record calcium fluctuations during this task as a proxy for neuronal activity. Distractor stimuli caused rats to interrupt their consumption of saccharin, a behavioural effect which quickly habituated with repeat testing. VTA neural activity showed consistent increases to distractor presentations and, furthermore, these responses were greater on distracted trials compared to non-distracted trials. Interestingly, neural responses show a slower habituation than behaviour with consistent VTA responses seen to distractors even after they are no longer distracting. These data highlight the complex role of the VTA in maintaining ongoing appetitive and consummatory behaviours while also monitoring the environment for salient stimuli.

Download Full-text

Disruptions in effort-based decision-making following acute optogenetic stimulation of ventral tegmental area dopamine cells

10.1101/2020.12.09.417832 ◽

2020 ◽

Author(s):

Benjamin R. Fry ◽

Nathan T. Pence ◽

Andrew McLocklin ◽

Alexander W. Johnson

Keyword(s):

Decision Making ◽

Tyrosine Hydroxylase ◽

Ventral Tegmental Area ◽

Dopamine System ◽

Laser Stimulation ◽

Optogenetic Stimulation ◽

Ventral Tegmental ◽

Stimulation Of

AbstractThe dopamine system has been implicated in decision-making particularly when associated with effortful behavior. We examined acute optogenetic stimulation of dopamine cells in the ventral tegmental area (VTA) as mice engaged in an effort-based decision-making task. Tyrosine hydroxylase-Cre mice were injected with Cre-dependent ChR2 or control eYFP in VTA. While eYFP control mice showed effortful discounting, laser stimulation of dopamine cells in ChR2 animals disrupted effort-based decision-making by reducing choice towards the lever associated with a preferred outcome and greater effort, without affecting discrimination processes or nonspecific motoric behaviors. These findings suggest increases in dopamine activity can disrupt effort-based decision-making.

Download Full-text

Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder

Anesthesiology ◽

10.1097/aln.0000000000002667 ◽

2019 ◽

Vol 130 (6) ◽

pp. 923-935 ◽

Cited By ~ 7

Author(s):

Virginie Sterpenich ◽

Sonia Vidal ◽

Jeremy Hofmeister ◽

Giorgio Michalopoulos ◽

Victor Bancila ◽

...

Keyword(s):

Neural Networks ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Ventral Tegmental Area ◽

Emotional Processing ◽

Judgment Task ◽

Treatment Resistant ◽

Major Depressive ◽

Ventral Tegmental ◽

The Impact

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Ketamine rapidly improves maladaptive mood states in major depressive disorder, and some of the neural substrates underlying this therapeutic effect have been identified. This study aimed to identify functional changes within neural networks that may underlie the impact of ketamine on both reward and emotional processing in patients with treatment-resistant major depression. Methods Ten adult patients with a Montgomery–Åsberg Depression Rating Scale score above 25 were enrolled to receive a single intravenous administration of ketamine (0.5 mg/kg). Patients’ performance along with related neural network activations were analyzed in a game-like reward task and in an emotional judgment task using functional magnetic resonance imaging 1 day before and 1 and 7 days after ketamine administration. Results A significant correlation (R2 = 0.46, P = 0.03) between the improvement of depression scores and the enhanced reaction time for positive items was found in the game-like reward task 1 day after ketamine administration. This enhanced sensitivity for rewarded items was accompanied by increased activity of reward-related brain regions, including the orbitofrontal cortex, ventral striatum, and the ventral tegmental area, an effect that persisted up to 1 week after ketamine injection. In the emotional judgment task, it was found that ketamine rapidly modified local brain activities in response to emotionally negative, positive, or neutral stimuli in the amygdala, insula, anterior cingulate cortex, and in the ventral tegmental area. Conclusions Single bolus ketamine administration rapidly triggers lasting changes in mesolimbic neural networks to improve pathologic reward and emotional processing in patients with major depressive disorder.

Download Full-text

In utero Exposure to Anesthetics Alters Neuronal Migration Pattern in Developing Cerebral Cortex and Causes Postnatal Behavioral Deficits in Rats

Cerebral Cortex ◽

10.1093/cercor/bhz065 ◽

2019 ◽

Vol 29 (12) ◽

pp. 5285-5301 ◽

Cited By ~ 3

Author(s):

V Gluncic ◽

M Moric ◽

Y Chu ◽

V Hanko ◽

J Li ◽

...

Keyword(s):

Neuronal Migration ◽

Cortical Neurons ◽

In Utero ◽

Acid Decarboxylase ◽

In Utero Exposure ◽

Oxygen Control ◽

Pregnant Rats ◽

Behavioral Deficits ◽

Proliferative Zone ◽

The Impact

Abstract During fetal development, cerebral cortical neurons are generated in the proliferative zone along the ventricles and then migrate to their final positions. To examine the impact of in utero exposure to anesthetics on neuronal migration, we injected pregnant rats with bromodeoxyuridine to label fetal neurons generated at embryonic Day (E) 17 and then randomized these rats to 9 different groups receiving 3 different means of anesthesia (oxygen/control, propofol, isoflurane) for 3 exposure durations (20, 50, 120 min). Histological analysis of brains from 54 pups revealed that significant number of neurons in anesthetized animals failed to acquire their correct cortical position and remained dispersed within inappropriate cortical layers and/or adjacent white matter. Behavioral testing of 86 littermates pointed to abnormalities that correspond to the aberrations in the brain areas that are specifically developing during the E17. In the second set of experiments, fetal brains exposed to isoflurane at E16 had diminished expression of the reelin and glutamic acid decarboxylase 67, proteins critical for neuronal migration. Together, these results call for cautious use of anesthetics during the neuronal migration period in pregnancy and more comprehensive investigation of neurodevelopmental consequences for the fetus and possible consequences later in life.

Download Full-text