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Studies Dissect Depression’s Circuitry

12 January 2013. With its wide range of symptoms and variable severity, depression might seem hopelessly complicated. But a spate of recent studies suggests that this complexity is resolvable at the brain circuit level. A trio of papers in Nature—two from Karl Deisseroth's group at Stanford University in Palo Alto, California, and one from Ming-Hu Han's laboratory at Mount Sinai School of Medicine in New York City—uses optogenetics to dissect the serotonergic and dopaminergic contributions to depression-related behaviors in rodents. A fourth paper in the American Journal of Psychiatry led by Richard Davidson at the University of Wisconsin in Madison reports that antidepressants help sustain activity in the nucleus accumbens (NAc), as well as connectivity between frontal cortex and the striatum

The results offer a more refined picture of the brain basis of depression by piecing together how various brain regions already implicated in the disorder might interact. For example, brain imaging studies have found an underactive medial prefrontal cortex (mPFC) in depression, and stimulating it has antidepressant-like effects in humans and rodents alike (e.g., Mayberg et al., 2005; Hamani et al., 2010). As the place where high-level cognition happens and goal-directed behaviors are hatched, however, the mPFC projects widely throughout the brain, making it hard to discern the relevant pathways.

The optogenetics studies, with their ability to switch specified neurons on and off (see SRF related news story) help resolve this—in rodent models of depression, at least. The first study finds that activating connections between mPFC and the serotonin-containing neurons of the dorsal raphe nucleus (DRN) can shake rats out of passive states that have been related to depression. The second and third optogenetics studies center on the midbrain dopamine neurons, and find roles—albeit contradictory—for their phasic activation in depression-related phenotypes, and parse the involvement of ventral tegmental area (VTA) connections with mPFC and NAc. The fourth paper, a human brain imaging study, looks more closely at the time course of activation of the NAc, and frontal-striatal connectivity before and after antidepressant treatment.

At the serotonergic source
In the first study, published online 18 November, first author Melissa Warden and colleagues monitored how rats reacted to the forced swim test, a common measure of depression-related responses. Rodents are placed in a tank of water from which they cannot escape, and they respond to this undesirable situation with either swimming (considered a proactive response) or immobile floating (a passive response). At the very least, the test is predictive of antidepressant response, with antidepressants swaying behavior toward more swimming (Cryan et al., 2005).

Using rats made to express the light-sensitive channel channelrhodopsin-2 in mPFC neurons, the researchers found that illuminating mPFC did not alter the rats’ behavior during the forced swim test. Noting that the antidepressant-like effect of mPFC stimulation requires intact serotonin systems (Hamani et al., 2010), the researchers next tried a more selective mPFC activation, targeting only those mPFC neurons projecting to the serotonin-containing DRN. Activating this pathway boosted swimming, which tracked with the on/off pattern of light. When the mPFC-DRN connection was activated on dry land, however, no light-induced movement emerged, suggesting that this connection promoted a proactive behavioral state rather than simply driving locomotion.

The researchers also targeted mPFC projections to the lateral habenula (LHb), a subcortical region implicated in depression that connects to dopamine and serotonin-containing neurons. Selectively activating mPFC-LHb projections decreased the amount of swimming, suggesting that passive states are also actively driven by mPFC neurons (see SRF related news story).

Dopamine bursts onto the scene
In the second paper, published online 12 December, first authors Dipesh Chaudhury and Jessica Walsh of Han’s lab focused on the dopamine-containing neurons of the VTA, which were made to express channelrhodopsin-2 in mice. Previous studies have found that the pattern of spiking in these neurons matters, with phasic, high-frequency bursts encoding reward signals and phasic activity more commonly found in mice susceptible to the ill effects of a social-defeat stress model of depression. This paradigm places a mouse in the same cage as an older mouse, which attacks the younger mouse for two minutes. After repeated bouts of this bullying, “susceptible” mice begin to show a lack of interest in social interactions and sucrose, whereas “resilient” mice do not.

The researchers found that phasic activation of the VTA dopamine neurons during the social defeat paradigm increased susceptibility to its depression-like effects, but tonic, evenly spaced patterns of activation did not. In fact, phasic activation could convert resilient mice to susceptible mice: those mice who had normal social interaction and sucrose preference after 10 days of social defeat stress could suddenly lose interest in other mice and sucrose upon phasic activation of their VTA dopamine neurons.

Next, the researchers parsed the dopamine pathways contributing to susceptibility. Phasic activation of the VTA’s connection with the NAc produced decreases in social interaction and sucrose preference, whereas inhibition of this connection promoted resilient responses. In contrast, phasic activation of the VTA’s connection with the mPFC had no effect, but inhibiting it produced susceptibility. This suggests that the VTA participates in complementary circuits that produce opposite effects on depression-related behaviors.

Or dopamine for depression relief?
In the third paper, first authors Kay Tye, Julie Mirzabekov, and Melissa Warden of Deisseroth’s lab focused on the role of dopamine neurons of the VTA in producing a collection of depression-like behaviors in rodents. Optogenetically inhibiting these neurons resulted in an abrupt decrease in escape-related behavior in the tail-suspension test, and a decrease in sucrose preference. When these behaviors were induced with chronic mild stress (e.g., overcrowded housing, white noise, and continuous cage illumination), phasically activating VTA dopamine neurons could reverse these depression-like behaviors.

Though this indicates that the depression-like responses in the chronic mild stress paradigm recruit the same dopamine VTA circuitry, it is not consistent with the findings from Han’s lab, which related increased phasic activation to depression-like outcomes. The authors note that both increased and decreased dopamine VTA firing have been related to depression, and they suggest that this may reflect the different models used. “It is important to emphasize in this context that the effects of stress on the mesolimbic dopamine system are highly complex, as different stressors can cause opposite responses from VTA neurons depending on pre-exposure and severity,” they write.

Antidepressants sustain brain activation
The fourth study, published online 7 December, examined the time course of brain activation in people with depression as they tried to boost their positive feelings in an emotion regulation task. Using functional magnetic resonance imaging (fMRI), first author Aaron Heller and colleagues asked whether depression was related to an inability to engage the relevant brain regions, or rather an inability to sustain their engagement. Their previous study had suggested the latter, with people with major depressive disorder lacking the sustained activation of NAc and frontal-striatal connectivity found in healthy controls (Heller et al., 2009). Building on this, the new study asked whether taking antidepressants helped sustain this activity. It did: two months of either venlafaxine or fluoxetine treatment increased the sustained activity in 21 depressed patients, and those with the largest gains also reported the largest increases in positive affect.

Together, the studies give rise to a picture of multiple, interacting circuits that contribute to the assortment of symptoms that characterize depression. Future research may reveal how one circuit could be favored over another, or how the tone of activity that normally runs through a circuit is determined. In the meantime, the studies suggest that new strategies for depression treatment may do well to be circuit specific, and temporally precise.—Michele Solis.

Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, Adhikari A, Tye KM, Frank LM, Deisseroth K. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature. 2012 Nov 18. Abstract

Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC, Pomeranz L, Christoffel DJ, Nectow AR, Ekstrand M, Domingos A, Mazei-Robison MS, Mouzon E, Lobo MK, Neve RL, Friedman JM, Russo SJ, Deisseroth K, Nestler EJ, Han MH. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2012 Dec 12. Abstract

Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, Kim SY, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten IB, Deisseroth K. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2012 Dec 12. Abstract

Heller AS, Johnstone T, Light SN, Peterson MJ, Kolden GG, Kalin NH, Davidson RJ. Relationships Between Changes in Sustained Fronto-Striatal Connectivity and Positive Affect in Major Depression Resulting From Antidepressant Treatment. Am J Psychiatry. 2012 Dec 7. Abstract

Comments on News and Primary Papers
Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 16 January 2013
Posted 17 January 2013
  I recommend the Primary Papers

The Nature articles on the role of dopamine and depression add greatly to our understanding of this transmitter system in affective disorders. While on the surface such studies may be viewed as being opposite in nature, both are highly consistent with results from our lab and others. We (Valenti et al., 2011) and others have shown that strong, acute stressors can activate dopamine neuron activity; however, when measured after long bouts of inescapable stress or following an incubation period, the activity of these neurons is markedly depressed (Moore et al., 2001; Valenti et al., 2012; Chang and Grace, 2013). These studies suggest that dopamine system activation during the stressor may be a precedent for dopamine system downregulation following termination of the stressor. Indeed, in the uncontrollable chronic stress model and in the learned helplessness model of depression (Chang and Grace, 2012; Belujon et al., 2012), we have found that dopamine neuron population activity depression correlates with behavioral indices of depressive-like behavior in rats.

The data from the Han and Deisseroth laboratories are actually highly consistent with these data. Thus, Han showed that phasic activation of dopamine neurons potentiates the effects of stress on subsequent depression (consistent with our studies showing dopamine activation during the initial stress events), whereas restoring dopamine activity during the depressed condition in Deisseroth's paper relieves the symptoms due to dopamine system downregulation.

Therefore, in our opinion, each phase of the depression process may have a dopamine component: an activation during the induction phase and an attenuation during symptom expression. Taken together, these findings provide unique insights into the process and expression of depression.


Belujon, P., Dollish, H.D. and Grace, A.A. (2012) Ketamine restores activity of the dopamine system selectively in rats exhibiting learned helplessness in an animal model of depression. Program No. 774.02.2012. Neuroscience Meeting Planner, New Orleans, LA. Society for Neuroscience, 2012. Online.

Chang, C.H. and Grace, A.A. (2012) Chronic mild stress induces anxiety-like behavior and down-regulation of dopamine system activity in rats. Program No. 774.13.2012. Neuroscience Meeting Planner, New Orleans, LA. Society for Neuroscience, 2012. Online.

Chang, C.-H. and Grace, A.A. (2013) Amygdala beta noradrenergic receptors modulate delayed down-regulation of dopamine activity following restraint. Journal of Neuroscience (in press).

Moore, H., Rose, H.J.. and Grace, A.A. (2001) Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons. Neuropsychopharmacology 24: 410-419. Abstract

Valenti, O., Lodge, D.J. and Grace, A.A. (2011) Aversive stimuli alter ventral tegmental area dopamine neuron activity via a common action in the ventral hippocampus. Journal of Neuroscience 31: 4280-4289. Abstract

Valenti, O., Gill, K.M. and Grace, A.A. (2012) Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: Response alteration by stress pre-exposure. European Journal of Neuroscience 35: 1312-1321. Abstract

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Comments on Related News

Related News: Synaptic Hyperactivity in the Lateral Habenula Linked to Depression

Comment by:  Alexander SartoriusAndreas Meyer-Lindenberg
Submitted 16 March 2011
Posted 16 March 2011

Deep midline structures of our brain seem to contribute considerably to risk for psychiatric illnesses (Northoff et al., 2010). The lateral habenula could be a bottleneck of information flow between midline and cortical structures. Since efferents of the lateral habenula influence all three monoaminergic systems, a contribution to depression risk has been hypothesized (Sartorius and Henn, 2007). One efferent pathway projects via the rostromedial tegmental nucleus to the ventral tegmental area (VTA). Dopaminergic neurons then project to the ventral striatum, reflecting a major part of the brain’s reward system.

The paper by Li et al. further characterizes this pathway by means of electrophysiology and narrows the gap to human depression. It is the first time that not only overactivation of the whole structure but excessive firing rates of specific neurons within the structure were observed in an animal model of depression. Furthermore, dendritic spine density of VTA-projecting neurons was elevated in congenitally helpless animals—an alteration that could reflect neuroplastic adaptations to a trait related to depression. In a final step of their work, Li et al. demonstrate that functional inhibition of the lateral habenula (by deep-brain stimulation—DBS) alleviates depressive-like behavior. This translational aspect may specify one mechanism that has contributed to full remission in our first severely depressed patient after DBS of the lateral habenula (Sartorius et al., 2010). That DBS of other structures within the reward system can efficiently treat depressive symptoms has been already demonstrated in a study by Bewernick et al., where especially aspects of anhedonia improved significantly (Bewernick et al., 2010). Consequently, these findings argue that anhedonia (Sanchis-Segura et al., 2005) should be quantified in further animal experiments exploring the DBS effects onto the reward pathway.

Other monoaminergic systems relevant for depression, such as the serotonergic and noradrenergic ones, should be explored next to fully understand the role of the habenula in orchestrating these fundamental neuromodulator circuits. The Network of European Funding for Neuroscience Research (NEURON) has recently funded a multinational project to further elaborate on the role of the habenula in risk for depression and the monoaminergic systems by means of functional human and animal imaging.


Northoff G, Wiebking C, Feinberg T, Panksepp J. The “resting-state hypothesis” of major depressive disorder-A translational subcortical-cortical framework for a system disorder. Neurosci Biobehav Rev. 2010 Dec 28. Abstract

Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, Axmacher N, Lemke M, Cooper-Mahkorn D, Cohen MX, Brockmann H, Lenartz D, Sturm V, Schlaepfer TE. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010 Jan 15;67(2):110-6. Abstract

Sanchis-Segura C, Spanagel R, Henn FA, Vollmayr B. Reduced sensitivity to sucrose in rats bred for helplessness: a study using the matching law. Behav Pharmacol. 2005 Jul;16(4):267-70. Abstract

Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, Henn FA, Meyer-Lindenberg A. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry. 2010 Jan 15;67(2):e9-e11. Abstract

Sartorius A, Henn FA. Deep brain stimulation of the lateral habenula in treatment resistant major depression. Med Hypotheses. 2007;69(6):1305-8. Abstract

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