The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism

Beas, B. Sofia; Wright, Brandon J.; Skirzewski, Miguel; Leng, Yan; Hyun, Jung Ho; Koita, Omar; Ringelberg, Nicholas; Kwon, Hyung Bae; Buonanno, Andrés; Penzo, Mario

doi:10.1038/s41593-018-0167-4

Cited by 136 publications

(191 citation statements)

References 47 publications

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“…After social defeat stress, which involves dopamine signaling in the NAc for the acquisition of stress responses, D 2 R‐SPN exhibited changes in the AMPA/NMDA ratios when mice were susceptible, suggesting that synaptic changes support sustained stress responses. A recent report showed that dopamine‐β‐hydroxylase‐positive neurons in the locus coeruleus project to the paraventricular thalamus to facilitate stress responses via dopamine release . According to the results of the study, stress caused a persistent decrease in inhibitory input to paraventricular thalamus neurons, which suggested that D 2 R‐dependent LTD underlies such persistent effects.…”

Section: Cellular and Synaptic Bases For Sustained Effectsmentioning

confidence: 62%

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

Yagishita

2019

Psychiatry Clin Neurosci

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Pharmacological studies of antidepressants and atypical antipsychotics have suggested a role of dopamine and serotonin signaling in depression. However, depressive symptoms and treatment effects are difficult to explain based simply on brain‐wide decrease or increase in the concentrations of these molecules. Recent animal studies using advanced neuronal manipulation and observation techniques have revealed detailed dopamine and serotonin dynamics that regulate diverse aspects of motivation‐related behavior. Dopamine and serotonin transiently modulate moment‐to‐moment behavior at timescales ranging from sub‐second to minutes and also produce persistent effects, such as reward‐related learning and stress responses that last longer than several days. Transient and sustained effects often exhibit specific roles depending on the projection sites, where distinct synaptic and cellular mechanisms are required to process the neurotransmitters for each transient and sustained timescale. Therefore, it appears that specific aspects of motivation‐related behavior are regulated by distinct synaptic and cellular mechanisms in specific brain regions that underlie the transient and sustained effects of dopamine and serotonin signaling. Recent clinical studies have implied that subjects with depressive symptoms show impaired transient and sustained signaling functions; moreover, they exhibit heterogeneity in depressive symptoms and neuronal dysfunction. Depressive symptoms may be explained by the dysfunction of each transient and sustained signaling mechanism, and distinct patterns of impairment in the relevant mechanisms may explain the heterogeneity of symptoms. Thus, detailed understanding of dopamine and serotonin signaling may provide new insight into depressive symptoms.

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Section: Cellular and Synaptic Bases For Sustained Effectsmentioning

confidence: 62%

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

Yagishita

2019

Psychiatry Clin Neurosci

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“…For these studies, the effects of PrL-PVT manipulation were examined early in Pavlovian training, when Pavlovian cues are known to evoke a DA response in the NAc to a different degree in STs and GTs 28,56 . Although we expected to observe more robust behavioral effects during this period, we found that stimulation of the PrL-PVT pathway early in Pavlovian training did not affect the behavior of STs, nor did it significantly affect extracellular It has become increasingly apparent in recent years that the PVT and its associated circuitry play an important role in motivated behaviors, including those related to addiction and anxiety-related disorders 16,33,[57][58][59][60][61][62][63][64][65][66][67][68] . Here, we honed in on the PrL-PVT pathway and exploited an animal model of individual differences in cue-reward learning to demonstrate that this circuit acts as a top-down control mechanism to suppress the attribution of incentive value to a food-paired cue.…”

Section: Discussionmentioning

confidence: 72%

The Paraventricular Thalamus is a Critical Mediator of Top-down Control of Cue-motivated Behavior in Rats

Campus

Covelo

Kim

et al. 2019

Preprint

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Stimuli or cues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the signtracker/goal-tracker animal model. Goal-trackers attribute predictive value to rewardcues, and sign-trackers attribute both predictive and incentive value. Using chemogenetics and microdialysis, we show that, in sign-trackers, stimulation of the neuronal pathway from the prelimbic cortex (PrL) to the paraventricular nucleus of the thalamus (PVT) decreases the incentive value of a reward-cue. In contrast, in goaltrackers, inhibition of the PrL-PVT pathway increases both the incentive value and dopamine levels in the nucleus accumbens shell. The PrL-PVT pathway, therefore, exerts top-down control over the dopamine-dependent process of incentive salience attribution. These results highlight PrL-PVT pathway as a potential target for treating psychopathologies associated with the attribution of excessive incentive value to reward-cues, including addiction. independent delivery of food-US, distinct conditioned responses emerge. Some rats, goal-trackers (GTs), approach the location of impending food delivery upon the lever-CS presentation, while others, sign-trackers (STs), approach and interact with the lever-CS itself. For both GTs and STs the lever-CS acquires predictive value and elicits a conditioned response, but for STs, the CS also acquires incentive value. This animal model, therefore, provides a unique platform to investigate the neurobiological determinants of individual differences in the propensity to attribute incentive salience to reward-cues.Previous studies suggest that sign-tracking behavior results from enhanced activity in subcortical brain circuits known to mediate motivated behaviors, including the striatal dopamine system, the amygdala, and the hypothalamus 22,23,28-31 . In addition, relative to GTs, STs appear to have deficits in top-down cognitive control originating in the prefrontal cortex 32 . Thus, we hypothesize that sign-tracking behavior arises from an imbalance between top-down cognitive control and bottom-up motivational processes.One brain region that is ideally situated to act as a fulcrum between cortical, limbic and homeostatic circuits is the paraventricular nucleus of the thalamus (PVT). The PVT has, in fact, come to be known as the "thalamic gateway" 33 for appetitive motivation; acting to integrate cognitive, emotional, motivational and viscerosensitive information, and, in turn, guide behavioral responses 33,34 . Consistent with this view, the PVT has been implicated in the propensity to attribute incentive motivational value to reward-cues [35][36][37] .The functional connectivity of the PVT in response to cue-induced neuronal activity differentiates STs from GTs 28,29,35 . In STs, cue-induced activity in the PVT is correlated with activity in subcortical areas, including the nucleus accumbens (NAc); whereas in GTs, cue-...

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“…Neurons in the LC are topographically organized based on their widespread efferent projections 46,47 , and circuit-based approaches reveal functional specificity of sub-populations of LC neurons based on their target projection regions 5,[12][13][14][15][16]18,19,67,68 . LC neurons appear to form neuronal ensembles, which can be activated in response to isolated sensory stimuli 67,69 .…”

Section: Adrenoceptor Distribution As An Organizing Principle Affordimentioning

confidence: 99%

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation

Zerbi

Floriou-Servou

Markicevic

et al. 2019

Preprint

107

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The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain, regulates many fundamental brain functions, and is implicated in several neuropsychiatric diseases. Although selective manipulation of the LC is not possible in humans, studies have suggested that strong LC activation might shift network connectivity to favor salience processing. To test this hypothesis, we use a mouse model to study the impact of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics". LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. We reveal a direct correlation between functional connectivity changes and transcript levels of alpha-1, alpha-2, and beta-1 adrenoceptors across the brain, and a positive correlation between NE turnover and functional connectivity within select brain regions. These results represent the first brain-wide functional connectivity mapping in response to LC activation, and demonstrate a causal link between receptor expression, brain states and functionally connected large-scale networks at rest. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection. RESULTSTo selectively target the LC, we used transgenic mice that express codon-improved Crerecombinase (iCre) under the dopamine-beta-hydroxylase (DBH) promoter (DBH-iCre mice, Figure 1A) 33 . We stereotactically delivered floxed excitatory DREADDs 34 (AAV5-hSyn-DIO-hM3Dq-mCherry; hM3Dq-mCh) or a control virus (AAV5-hSyn-DIO-mCherry; mCh) to the LC, thus restricting virus expression to DBH-positive noradrenergic neurons of the LC (Figure 1B). We assessed successful LC activation using pupillometry, a highly sensitive and clinically relevant readout of LC activation [35][36][37] . After two minutes of baseline recording under light isoflurane anesthesia, we activated LC neurons by administering the potent DREADD activator clozapine at an ultra-low dose (0.03 mg/kg, i.p., Figure 1C) 38 . Within a minute of clozapine injection, we observed a strong increase in pupil diameter in the hM3Dq-mCh group, while pupil diameter of mCh mice did not change in response to clozapine injection and remained stable throughout the 10-minute recording session (Figure 1D-F). To show that our LC activation protocol is behaviorally relevant, we subjected mice to an open field test (OFT) immediately after clozapine injection and recorded their behavior for 30 minutes. In comparison to mCh mice, clozapine injection had profound effects on the behavior of hM3Dq-mCh mice. Several minutes after clozapine administration, hM3Dq-mCh mice showed strongly suppressed locomotor activity ( Figure 1G, H), spent less time in the (more aversive) center of the open field (Figure 1I, J), performed less activity-related supported rears (Figure 1...

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The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism

Cited by 136 publications

References 47 publications

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

The Paraventricular Thalamus is a Critical Mediator of Top-down Control of Cue-motivated Behavior in Rats

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation

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