Nature sub-issue: Han Minghu's team reveals that VTA-BLA projection neurons encode anxiety rather than depressive behavior

Recently, Han Minghu's team from the School of Life and Health, Shenzhen University of Technology, Chinese Academy of Sciences (tentative name, hereinafter referred to as "Shenzhen Science and Technology") and the Institute of Brain Cognition and Brain Diseases, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, presented on Nature Communications (IF 14.
9) under Nature Published the latest research results entitled "Midbrain projection to the basolateral amygdala encodes anxiety-like but not depression-like behaviors"
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revealed that ventral tegmental area (VTA) dopamine (DA) neurons projecting to the basolateral amygdala (BLA) encode anxiety-like behaviors but not depression-like behaviors
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Furthermore, VTA-BLA dopamine neurons selectively control anxiety-related behaviors both in anxiety-alone conditions and in anxiety/depression comorbid conditions
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Figure 1 Screenshot of the first page of the paper.
This study opens up a new avenue for the treatment of anxiety disorders and anxiety/depression comorbidities caused by VTA-BLA circuit dysfunction
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Prof.
Minghu Han of SMI is the independent corresponding author of the paper, and the first author of the paper, Dr.
Carole Morel, is a postdoctoral fellow of Prof.
Han and is currently a research assistant professor at Mount Sinai School of Medicine in New York
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 Anxiety disorders are the most common mental illness, afflicting 273 million people worldwide
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The symptoms of anxiety disorders are complex and heterogeneous, and their etiology is poorly understood
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In addition, a large number of people with anxiety disorders also experience depressive symptoms, which complicates the study of neurological dysfunction in anxiety disorders
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 Studies have shown that the maintenance of healthy mental function is closely related to the activity of VTA DA neural circuits
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Neurons in this loop encode behaviors related to rewarding and aversive stimuli and support adaptive behavior
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In doing so, VTA DA neurons utilize circuits that project to brain regions associated with emotion, including projections to regions such as the amygdala (AMG), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC)
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However, the function of the VTA subcircuit in anxiety disorders has not been resolved in the context of anxiety alone or in anxiety/depression comorbidities
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In addition to the NAc and PFC regions, VTA DA neurons also project to the amygdala subnuclei, which include the BLA, a key brain structure associated with mood and anxiety
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While dopamine is known to play an important role in regulating BLA activity, the role of VTA-BLA DA neurons in regulating anxiety behavior is unclear
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Furthermore, the chronic social frustration stress (CSDS) model can induce heterogeneous individual behavioral phenotypes in mice
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In this model, although all mice experienced equal CSDS social stress, only a subset of susceptible mice exhibited depression-related behaviors such as social avoidance, anhedonia, circadian rhythm disturbance, and abnormal reward learning; the remaining mice, termed Resilient mice, without the above behavior
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Interestingly, both susceptible and resilient mice displayed an anxiety-like phenotype, suggesting that depression- and anxiety-related behaviors may be regulated by distinct neural circuits
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In order to explore the neural mechanisms behind anxiety phenotypes under anxiety alone and anxiety/depression comorbid conditions, Prof.
Han's team used CSDS to induce heterogeneous phenotypes in mice, namely AD mice with combined anxiety and depression phenotypes and AD mice showing only anxiety-like phenotypes Type A mice, AD mice exhibited depression-like behavior, that is, decreased social interaction, compared with control and A mice
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On the other hand, both AD and A mice exhibited anxiety-like behavior, i.
e.
decreased time in the elevated plus maze (EPM) open arms and in the center of the mine
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Correlation analysis showed that social interaction behaviors were not correlated with time in the EPM open arms and in the center of the mine, suggesting a lack of additive effect between depression-like and anxiety-like behaviors (Figure 2)
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These results suggest that the depression-like and anxiety-like behaviors that occur in mice after CSDS may be controlled by different neural mechanisms
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CSDS-induced anxiety-related behaviors did not correlate with depression-related social avoidance behaviors.
To search for the neural mechanisms of anxiety-like behaviors, the team focused on anxiety-related brain nuclei, AMG, retrogradely labeled VTA-BLA DA neurons and examined their Basal firing frequency, it was found that compared with the control group, the basal firing frequency of AD and A mice was significantly reduced (Figure 3)
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Compared with the control group, the excitability of VTA-BLA DA neurons in AD and A groups was also decreased, and the hyperpolarization-activated cation current Ih accompanied by excitability was significantly smaller
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Further correlation analysis revealed that VTA-BLA DA neuron activity was not associated with social interaction behavior, but was significantly associated with EPM open-arm time
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These physiological and behavioral data support the hypothesis that VTA-BLA DA neurons may selectively mediate CSDS-induced anxiety-like behaviors
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Anxiety-like behaviors were significantly correlated with the activity of VTA-BLA DA neurons.
To test whether there was a causal relationship between VTA-BLA DA neuron activity and anxiety-related behaviors, the team used optogenetics to bidirectionally modulate these neurons and measure their effect on behavior.
effects (bidirectional optogenetic manipulation of inhibitory NpHR or excitatory ChR2)
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The study found that yellow light stimulation in NpHR mice selectively inhibited the activity of VTA-BLA neurons, mimicking the reduction of the basal firing frequency of VTA-BLA DA neurons by about 50%, which could induce an anxiety-like phenotype (Figure 4)
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Conversely, when ChR2 mice were given blue light stimulation, which increased the firing of VTA-BLA DA neurons, CSDS-treated ChR2 mice spent more time in the open arms and spent more time in the center of the mine than control mice.
also increased, but ChR2 blue light stimulation did not alter social avoidance behavior in mice
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These optogenetic findings suggest that VTA-BLA DA neurons selectively control anxiety-like behaviors but not depression-related behaviors
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In conclusion, this work provides important information for the establishment of a brain map of affective disorders in the midbrain dopamine system
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VTA-BLA Neuron Activity Controls Anxiety-Like Behaviors Prof.
Minghu Han is the Executive Director of the Department of Mental Health and Public Health at the School of Life and Health of Deepin Science and Technology, and a former tenured professor at Mount Sinai School of Medicine in New York
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He has been engaged in the research of neuropsychiatric diseases for a long time.
His research expounds the susceptibility/resilience neural mechanism of individuals suffering from depression or maintaining physical and mental health under long-term stress environment, and identifies new drug targets Kv7/KCNQ potassium ion for depression treatment channel, and related research has entered clinical trials
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The research work published in Cell in 2007 established a classic animal model for the study of susceptibility and stress resistance mechanisms in the field
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At present, the latest research is another important achievement of the team based on the previous foundation to continue to explore the individual differences of stress response and its clinical
application
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Paper link: https://