Injury to one side of the brain can cause abnormalities in posture or movement on the opposite side of the body. These effects, which are sometimes seen in people who have suffered a stroke or head trauma, have typically been attributed to neural pathways that link the right side of the brain to spinal cord neurons controlling muscles on the left side of the body, and vice versa. 

But in a new study on rats that had their spinal cords severed, researchers claim to have discovered another, parallel pathway that triggers opposite-side effects following brain injury and might instead operate via hormones circulating in the blood. The work was published last month (August 10) in eLife.

The findings are “interesting and surprising,” says S. Thomas Carmichael, a neurologist at the University of California, Los Angeles, who was not involved in the work. While this type of proof-of-concept animal study has limited clinical relevance, he adds, the team’s report highlights what could be a novel physiological mechanism. “It puts it on the map as something tractable and worth studying.”

Georgy Bakalkin, a neurobiologist at Uppsala University and author on the new study, tells The Scientist that he has long been interested in the idea that hormones can have effects specific to one side of the body, but that it hasn’t really taken off in neuroscientific fields. While the nervous system is clearly lateralized—the spinal cord is known to be split into left and right, for example—a similar role for hormones in mediating side-specific effects of brain injury or other physiological signals has typically been disregarded, he says. 

Looking for such effects in their latest study, Bakalkin and colleagues set up an experiment in which they severed the spinal cords of rats, cutting the main pathway between the brain and the neurons controlling the hind limbs. Then they damaged one side of the brain by surgically removing a small section of the area that controls hind-limb movement.

In rats with intact spinal cords, this kind of one-sided brain injury causes abnormal posture and reflexes in the back leg on the opposite side of the animal’s body. In their paper, the researchers report that the same effect occurs in rats that had had their spinal cords cut, suggesting that the cut part of the spinal cord is somehow bypassed in these animals. (Control animals that had only their spinal cords cut but no brain injury didn’t show the same asymmetry in hind limb responses, Bakalkin says.)

The team next removed the pituitary gland, which releases various hormones from the brain, and repeated their main experiment. In this case, rats with severed spinal cords didn’t show abnormal leg posture following brain injury.

[It] shows proof of concept that not everything that happens in the context of brain injury is through the spinal cord in terms of limb function.

—Ramesh Raghupathi, Drexel University

The findings suggest that pituitary hormones are helping transmit information about brain injury to neurons controlling limb movement—something they might do by traveling through the blood to bind to hormone receptors on spinal neurons downstream of where the cut was made, Bakalkin says. 

One way this mechanism could result in asymmetrical limb responses would be if the right and left sides of the brain trigger release of different hormones in response to injury, and if the receptors for these hormones are asymmetrically distributed on the spinal cord, such that a right-brain hormone targets the left spinal cord and vice versa.

The researchers didn’t test this idea directly, although they report in their paper that injecting healthy rats with particular pituitary hormones or with blood from brain-injured animals recapitulated the side-specific limb abnormalities. In particular, the hormones β-endorphin and Arg-vasopressin caused the right back leg, but not the left back leg, to contract, they report.

If similar mechanisms operate in humans, it’s conceivable that drugs blocking receptors for particular hormones could help treat some of the physical effects of brain injury, Bakalkin adds. Indeed, in a follow-up experiment, the team reported that drugs inhibiting certain hormone receptors eliminated the hind-leg response in rats that had cut spinal cords and brain injury.

Ramesh Raghupathi, a neuroscientist at Drexel University who was not involved in the work, tells The Scientist that the team’s findings may dovetail with recent research identifying systemic imbalances in pituitary hormones following brain injury. “People have noticed that in patients,” he says, “but it’s never been translated, or reverse translated, into animal studies.”

He adds that for neuroscientists, these kinds of systemic effects are “one of those things that’s there in the background that we recognize. But we never really paid attention to it per se.” While this study is only in rats, he notes that it “shows proof of concept that not everything that happens in the context of brain injury is through the spinal cord in terms of limb function, and that there are external factors.”

Both Raghupathi and Carmichael point out that the team used clear and simple methods, as is appropriate for a proof-of-concept study, but that many aspects of the work, including the type of brain lesion, aren’t relevant to the kinds of injuries seen in humans.

Most of the team’s observations were made over a period of hours, Carmichael says, while the effects of brain injury emerge in people over weeks and months, “so there’s a temporal element that they haven’t even approached.” It’s also unclear how hormones might carry information about brain injury. They could perhaps trigger changes in synaptic strength or in the structural organization of neurons controlling motor responses, Carmichael says, but “it’s hard to know exactly what the actual cellular mechanism is.”

Bakalkin agrees that there’s more to be done to investigate the mechanisms underlying the effects his group reported. In addition to identifying specific hormones released following brain injury, the researchers want to work out how those hormones encode information about the side of the brain, and how that could translate into side-specific effects on limbs. The team has also been running experiments to make extra sure they haven’t missed any other neural pathways that could bypass the spinal cord cut.

In the meantime, the study’s a useful reminder for researchers using animal models that left and right aren’t necessarily equivalent, Raghupathi says. “When people do unilateral brain injuries, some people do the left side, some people do the right side,” he says. “There’s always been this idea that for a rat, it really doesn’t matter.”