Homing In on the Brain’s “Cuddling” Circuitry

Prairie voles are role models for monogamy. Unlike most other mammals these adorable, mouselike creatures typically mate for life, raising their young together and spending time cuddling in their home nests. In a series of experiments published this week in Nature researchers report they have pinpointed a particular brain circuit that may drive formation of these social bonds. What’s more, they discovered they could manipulate this affection: When they artificially activated that brain pathway, it spurred prairie voles to form pair-bonds even in the absence of sex—normally a prerequisite.

The brain circuit they identified had previously been linked to learning, which suggests social bonding itself is a form of mental training. The hope now is that if this same basic bonding mechanism is at work in humans, doctors could one day therapeutically boost those pathways in people with impairments in this ability, says senior author Robert Liu of Emory University.

Until now most social-bonding research has zeroed in on the neurotransmitters oxytocin and vasopressin—hormones that play key roles in the formation of social bonds. But this new discovery takes that work another step forward to map out exactly what happens between particular brain areas while animals are engaged in the positive social interactions that lead to long-lasting bonds, Liu says.

The work hinged on some unique aspects of vole behavior: Prairie vole interactions differ greatly from those of their close cousins, the mouse and the rat. Most mice or rats, when placed in a cage with an unfamiliar companion, will investigate the stranger intensely. When those same rodents are placed together again, however, the visitor will ignore the no-longer-novel animal.

Prairie voles, in contrast, will spend more time with a companion with each exposure and will engage in more intimate behaviors such as snuggling. To determine just how much voles like each other, researchers typically measure the time voles spend “huddling,” a behavior in which the furry friends snuggle up to each other and remain motionless. “It’s like they’re just vegging out together,” says Liu. The more time the voles spend together, the more they huddle. Huddling among opposite-sex voles, he says, often follows mating and leads to longer-term companionship.

To figure out what happens in the brain to make a familiar vole more attractive over time, Liu and his colleagues implanted electrodes in 15 female prairie voles’ brains and measured local field potentials, a readout of the activity of thousands of neurons near the electrode. Electrodes were placed in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAcc), two brain areas known to be anatomically connected and previously implicated in social bonding. Meanwhile, a control group of voles had electrodes implanted in the mPFC and in an area physically near the NAcc, but whose activity was not connected with it. None of the voles had previously pair-bonded with a mate, and the researchers only investigated heterosexual pairs.

After taking those baseline brain measurements, the researchers placed each female vole in a cage together with an unfamiliar male vole and collected video while recording the female’s neural activity. The recordings showed both the mPFC and the NAcc neurons displayed oscillatory brain activity at the same low frequency. “That’s called coherence, and it indicates [the two brain areas] may be talking to each other,” Liu says. Moreover, the recordings showed neurons firing in the mPFC modulated NAcc activity: The more strongly that circuit was activated, he says, the more quickly the prairie vole began huddling with her mate. Most voles had sex soon after being placed together, which sent those neural firings along this pathway into overdrive. “We think that mating tends to boost the circuit’s activity, and somehow helps switch the animal toward becoming affiliated,” Liu says.

Speed Dating

Next the team wanted to test whether activating this circuit could drive bonding even when mating did not occur. To do that, they used optogenetics—the first time the powerful technique has been employed to study the prairie vole. They injected the mPFC of 12 female prairie voles with a virus carrying the gene for channel rhodopsin 2, a protein that, when stimulated with light, causes neurons to “fire.” (A control group of 10 female voles received an injection with a gene for an inactive protein.)

The researchers then placed a tiny fiber-optic filament over the NAcc, so that flashes of light prompted firing only in those neurons that extended from the mPFC. They then designed a special cage in which a male was placed “in jail” inside a female vole’s cage. “They could see, smell and hear one another; they just couldn’t get it on,” Liu says. Whenever the female came in close proximity to the male, the researchers stimulated the mPFC inputs to the NAcc with a frequency pattern matching the one they had seen in their earlier recordings.

Normally prairie voles will not bond following a mere indirect exposure that does not involve physical contact. But the day after the optogenetic stimulation of the mPFC–NAcc circuit females preferred their “jail” partner to a strange male vole, indicating modulation of the circuit was enough to drive bonding. Control voles showed no preference for their jailed partners. Prairie voles normally form bonds for life but Liu says they only tested the optogenetically induced behavior after one day, so they do not know how long the artificial bond might last.

The NAcc is an important component of the brain’s reward center, and prior research has proved that stimulating the NAcc in awake animals, including rodents and primates, causes them to form an immediate preference for whatever is in their vicinity at the time. “When you activate that brain area, it makes you like what you see,” says Robert Froemke, a neuroscientist at New York University who was not involved in the study. But by using optogenetics, the researchers did not simply stimulate the NAcc—they selectively turned on inputs from the mPFC that naturally modulate NAcc activity during bonding, and they showed that such activation was sufficient to form at least a short-term bond.

The Emory team has not yet examined the neurotransmitters involved in the mPFC–NAcc signaling but they suspect key roles for oxytocin and dopamine, neurotransmitters used in the brain’s reward system, both of which they plan to study next. “Fundamentally, this teaches us about how bonding occurs in general,” says Steven Phelps, a social bonding researcher at The University of Texas at Austin who also did not participate in the work. This type of circuit activity has been demonstrated before in learning, but “the extension to social bonding is a logical but very new insight.”


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