Abstract
Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence - in real time - linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 532-536 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 493 |
| Issue number | 7433 |
| DOIs | |
| State | Published - Jan 24 2013 |
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Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. / Chaudhury, Dipesh; Walsh, Jessica J.; Friedman, Allyson K.; Juarez, Barbara; Ku, Stacy M.; Koo, Ja Wook; Ferguson, Deveroux; Tsai, Hsing Chen; Pomeranz, Lisa; Christoffel, Daniel J.; Nectow, Alexander R.; Ekstrand, Mats; Domingos, Ana; Mazei-Robison, Michelle S.; Mouzon, Ezekiell; Lobo, Mary Kay; Neve, Rachael L.; Friedman, Jeffrey M.; Russo, Scott J.; Deisseroth, Karl; Nestler, Eric J.; Han, Ming Hu.
In: Nature, Vol. 493, No. 7433, 24.01.2013, p. 532-536.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons
AU - Chaudhury, Dipesh
AU - Walsh, Jessica J.
AU - Friedman, Allyson K.
AU - Juarez, Barbara
AU - Ku, Stacy M.
AU - Koo, Ja Wook
AU - Ferguson, Deveroux
AU - Tsai, Hsing Chen
AU - Pomeranz, Lisa
AU - Christoffel, Daniel J.
AU - Nectow, Alexander R.
AU - Ekstrand, Mats
AU - Domingos, Ana
AU - Mazei-Robison, Michelle S.
AU - Mouzon, Ezekiell
AU - Lobo, Mary Kay
AU - Neve, Rachael L.
AU - Friedman, Jeffrey M.
AU - Russo, Scott J.
AU - Deisseroth, Karl
AU - Nestler, Eric J.
AU - Han, Ming Hu
PY - 2013/1/24
Y1 - 2013/1/24
N2 - Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence - in real time - linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.
AB - Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence - in real time - linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.
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U2 - 10.1038/nature11713
DO - 10.1038/nature11713
M3 - Article
VL - 493
SP - 532
EP - 536
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7433
ER -