Anxiety-like behavior correlates with the hypoactivity of VTA → BLA dopamine neurons. a Experimental timeline. b Schematic of the brain surgery to dissect VTA → BLA circuit. c BLA surgery injection site (scale bar=500 μm). d Morphological validation showing the targeted VTA → BLA dopamine neurons in TH-BAC-Cre mice injected with AAVrg-DIO-eYFP (scale bar = 500 and 100 μm, representative images of the 23 recorded mice). e Sample traces of ex vivo cell-attached recordings from CTL, AD, and A mice (scale bar = 0.2 mV). f Spontaneous firing activity of VTA → BLA dopamine neurons in AD and A mice compared to control mice (mean ± s.e.m., ANOVA, F(2, 104) = 6.750 p = 0.0018; post hoc test, t = 3.48 p = 0.002; t = 3.50 p = 0.003, n = 30, 31, 45 neurons, n = 23 combined C57BL6/J and TH-BAC-Cre mice injected with AAVrg-DIO-eYFP and Green Luma, respectively). g Pearson correlation analyses of VTA → BLA dopamine neuron firing with the social interaction behavior after CSDS (p = 0.59, 3–7 neurons per mouse, n = 23 combined C57BL6/J and TH-BAC-Cre mice). h Pearson correlation analyses of VTA → BLA dopamine neuron firing activity with the time in EPM open arms (p = 0.0015, 3–7 neurons per mouse, n = 23 combined C57BL6/J and TH-BAC-Cre mice). i Sample traces of ex vivo whole-cell recordings from CTL, AD, and A mice at a 40 pA step current injection. j VTA → BLA dopamine neurons excitability in AD and A mice compared to CTL mice following incremental steps in currents injections (20–280 pA; mean ± s.e.m., RM two-way ANOVA: group effect: F(2, 33) = 3.818 p = 0.021; Interaction F(28, 434) = 3.164 p = 1.08e−07; post hoc tests: t = 2.41 p = 0.04; t = 2.53 p = 0.04; t = 1.95 p = 0.04; t = 2.63 p = 0.04; t = 1.64 p = 0.04; t = 2.52 p = 0.04; t = 1.72 p = 0.04; t = 2.25 p = 0.04; n = 11, 12, 14 neurons/4, 5, 6 TH-BAC-Cre mice). k VTA → BLA dopamine neurons rheobase in AD and A mice compared to CTL mice (mean ± s.e.m., ANOVA: Group effect: F(2, 33) = 4.016 p = 0.013; post hoc tests t = 2.43 p = 0.04; t = 2.85 p = 0.02; n = 11, 13, 14 neurons/4, 5, 6 TH-BAC-Cre mice). l VTA → BLA dopamine neurons hyperpolarization-activated current, i.e., Ih current in AD and A mice compared to CTL mice following incremental voltage steps (mean ± s.e.m., RM two-way ANOVA: group effect: F(2, 33) = 4.194 p = 0.017; interaction F(10, 175) = 3.393 p = 9.7e−06; post hoc tests t = 2.22 p = 0.04; t = 2.71 p = 0.025; n = 11, 13, 14 neurons/4, 5, 6 TH-BAC-Cre mice). m VTA → BLA dopamine neurons sag ratio in AD and A mice compared to CTL mice (mean ± s.e.m., ANOVA: group effect: F(2, 32) = 7.225 p = 0.001; t = 3.04 p = 0.009; t = 3.79 p = 0.002, n = 11, 13, 14 neurons/4–6 TH-BAC-Cre mice). In all panels, two-sided statistical analyses post hoc corrected tests were performed, *p < 0.05, **p < 0.01. Credit: Nature Communications (2022). DOI: 10.1038/s41467-022-29155-1
Anxiety disorders are the most common psychiatric illnesses. Some patients suffering from anxiety disorders also display depressive-like symptoms, leading to greater severity and complexity of anxiety disorders.
Recently, researchers from Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS) and Icahn School of Medicine at Mount Sinai have revealed the functional role for VTA→BLA dopamine neurons controlling anxiety-related behaviors not only in singular anxiety, but also in anxiety-depression comorbid conditions in mice.
This study was published in Nature Communications on March 22.
The chronic social defeat stress (CSDS) paradigm can induce singular or combined anxiety- and depressive-like phenotypes in mice. Based on this model, the researchers found that a ventral tegmental area (VTA) dopamine circuit projecting to the basolateral amygdala (BLA) selectively controlled anxiety-like but not depression-like behaviors.
Through circuit-dissecting ex vivo electrophysiology and in vivo fiber photometry approaches, they discovered that expression of anxiety-like not depressive-like phenotypes were negatively correlated with VTA→BLA dopamine neuron activity.
Furthermore, bidirectional optogenetic manipulation by using inhibitory NpHR or excitatory ChR2 demonstrated a causal link between such neuronal activity and anxiety-like behaviors.
This study provides new insights into the functional role of VTA→BLA dopamine neurons in selective regulation of anxiety-related behaviors.
More information:
Carole Morel et al, Midbrain projection to the basolateral amygdala encodes anxiety-like but not depression-like behaviors, Nature Communications (2022). DOI: 10.1038/s41467-022-29155-1
Citation:
Midbrain projection to the basolateral amygdala encodes anxiety-like behaviors (2022, March 30)
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