In a lab at Stanford University, a mouse is showing signs of depression. For around 10 weeks, it has experienced a series of irritations, from bouts without food or water, to erratic sleep patterns. Now, its motivation is low—when picked up by the tail, it makes few attempts to escape, and it doesn’t try to explore new spaces. It’s also less willing to sip from a sugary liquid– a sign that it gets less pleasure from normally pleasurable activities. It is never easy to assess the mental health of an animal, but this mouse is clearly showing some of the classic symptoms of depression.
But not for long.
Earlier, Kay Tye and Julie Mirzabekov altered the mouse so that a flash of light can activate a small part of its brain—the ventral tegmental area (VTA), near the bottom of the brain and close to the midline. A burst of light, and the mouse’s behaviour changes almost instantly. It struggles when held aloft, it explores open areas, and it regains its sweet tooth. A burst of light, and its symptoms disappear.
But on the other side of the country, at the Mount Sinai School of Medicine, Dipesh Chaudhury and Jessica Walsh are doing the same thing to completely different effect. Their mice have been altered in a similar way, so that light can also switch on their VTA neurons. But these rodents have endured a shorter but more intense form of stress—10 days of being placed in cages with dominant, aggressive rivals. Because of the resulting attacks, some of them have developed depressive symptoms. Others are more resilient. But when Chaudhury and Walsh flashed the VTAs of these mice, resilient individuals transformed into susceptible ones.
Both studies used the same methods to trigger neurons in the same part of the brain… and got completely different effects. In Tye and Mirzabekov’s experiment, depressed mice resumed their normal behaviour. In Chaudhury and Walsh’s study, the resilient mice showed more depressed symptoms.
Many routes to depression
Both teams think that the apparently contradicting results are due to the different types of stress experienced by the rodents. Tye’s animals experienced chronic mild stress, like a human might when facing constant job insecurity. Chaudury and Walsh’s mice faced severe “social-defeat” stress over a shorter time, which is more like someone getting mugged. These contrasting experiences might influence the same parts of the brain, but they do so in different ways. “Everyone has their own life history, and experiences different stress or traumas,” says Ming-Hu Han, who led the second study. “This may be why if you compare the symptoms in two people with depression, they’re different.”
These results underscore the complicated nature of depression. It has many potential causes that could act on the brain in opposite ways, even if they’re influencing the same area, and producing a similar constellation of symptoms.
This could also explain why there’s no one-size-fits-all treatment for depression. “Even the most effective drugs just work for a subset, and certain treatments work beautifully for some patients but make it worse for others,” says Tye, who now heads up her own lab at Massachussetts Institute for Technology. Research on antidepressants has been… well… a little depressing. Despite a five-decade history, very few advances have been made in the last decade. “Over the past half century, no genuinely groundbreaking progress has been made,” says Gal Yadid from Bar-Ilan University in Israel.
But these new studies, although they were done in mice, provide many clues that could lead to new treatments. They pinpoint parts of the brain that are involved in symptoms, they show that those symptoms can potentially be reversed very quickly, and they tell us more about the chemicals that are involved.
Most of the current wave of antidepressants, like Prozac, increase levels of the brain chemical serotonin, on the basis that low levels lead to depression. But this hypothesis can’t be entirely right. For a start, these drugs don’t work for everyone. And when they do, they can take months to kick in. If the drugs were working because they boosted serotonin levels, they should work within hours. As it is, it looks like they’re acting indirectly.
We can do better. Studies with deep-brain stimulation, where a implanted device electrically stimulates the brain, have shown that depression symptoms can be reversed very quickly. The same happens with some drugs like ketamine, albeit with severe side effects. So, it’s clearly possible to get an antidepressant effect in the brain very quickly; it’s just a case of targeting the right circuits. Based on the two new studies, it looks like those circuits reside in the VTA, and specifically in its connections to the nearby nucleus accumbens (NA).
The VTA is a hub for neurons that secrete dopamine, another brain chemical that’s involved in feelings of reward. Dopamine is a relatively new player in depression research. Over the last decade, various groups have manipulated the dopamine neurons connecting the VTA and NA and produced symptoms of depression in mice.
Tye and Chaudhury’s groups have effectively done the same, but with far more precision than anyone has previously managed. Their ace card was a technique called optogenetics, which implants neurons with light-sensitive proteins that allows them to be controlled by optic fibres. With these proteins, scientists can turn neurons on or off with different colours of light. They can target specific parts of the brain, or specific types of cell. They can investigate the brain like never before (and it’s no surprise that one of the technique’s inventors – Karl Deisseroth – features on both papers).
Tye’s group used optogenetics to first silence VTA neurons, which immediately and reversibly made normal mice behave as if they were depressed. Conversely, when they made the same neurons fire in regular bursts (“phasically”), they reversed symptoms in mice that had been mildly stressed for weeks.
Han’s group used optogenetics to show the opposite effects in mice that had experienced extreme “social defeat” stress for days. When they made the VTA neurons fire phasically, resilient animals showed depression-like symptoms. When they silence those same neurons, the susceptible animals became resilient.
The two flavours of stress might be doing opposite things, but they’re both acting on the VTA, and their effects can both be reversed immediately. “It proves unambiguously the importance of the dopamine system to depression,” says Yadid. He suspects that our serotonin-boosting antidepressants work by indirectly affecting dopamine levels. And if that’s the case, then targeting dopamine circuits directly should produce stronger, faster effects.
“We see effects in the order of seconds or minutes,” says Tye. “That tells us that we are targeting the direct circuits that are immediately governing depression-related symptoms.” In both cases, it wasn’t just the VTA that mattered, but its connections to the nucleus accumbens (NA). Signals from the VTA control the release of dopamine in the NA, and that in turn affects depression-like behaviour.
“That’s the target right there,” says Tye. She hopes that controlling this circuit—either with drugs, or with electrical stimulation—could lead us to better ways of treating depression, which would work very quickly and carry few side effects. “At the moment, we don’t have drugs that target specific brain regions, but it’s not beyond imagining,” she says.
References: Tye, Mirzabekov, Warden, Ferenczi, Tsai, Finkelstein, kim, Adhikari, Thompson, Andalman, Gunaydin, Witten & Deisseroth. 2012. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. http://dx.doi.org/10.1038/nature11740
Chaudhury,Walsh, Friedman, Juarez, Ku, Koo, Ferguson, Tsai, Pomeran, Christoffel, Nectow, Ekstrand, Domingo, Mazei-Robison, Mouzon, Lobo, Neve, Friedman., Russo, Deisseroth, Nestler & Han. 2012. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature http://dx.doi.org/doi:10.1038/nature11713
Dopamine neurons modulate neural encoding and expression of depression-related behaviour
Kay M. Tye, Julie J. Mirzabekov, Melissa R. Warden, Emily A. Ferenczi, Hsing-Chen Tsai, Joel Finkelstein, Sung-Yon Kim, Avishek Adhikari, Kimberly R. Thompson, Aaron S. Andalman, Lisa A. Gunaydin,Ilana B. Witten& Karl Deisseroth
- Published online12 December 2012
Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia1. Dopamine neurons involved in reward and motivation2, 3, 4, 5, 6, 7, 8, 9 are among many neural populations that have been hypothesized to be relevant10, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
Nature. 2012 Dec 12. doi: 10.1038/nature11713. [Epub ahead of print]
1] Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA .
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.