Post by lozgordon45 on Jul 20, 2023 4:30:56 GMT
Many papers about autism-linked genes note that the genes are expressed throughout both the central and the peripheral nervous systems. The proportion of such prolific genes may be as high as two-thirds, according to one 2020 analysis. Yet few studies delve into what those genes are actually doing outside the brain.
That’s starting to change. Although autism is typically thought of as a brain condition, a critical mass of researchers has started to investigate how the condition alters neurons elsewhere in the body. Their work — part of a broader trend in neuroscience to look beyond the brain — hints that the role of the peripheral nervous system in autism is, well, anything but peripheral: Neuronal alterations outside the brain may help to explain a host of the condition’s characteristic traits.
Much of the research so far focuses on touch and the workings of the gut, but there is increasing interest in other sensory and motor neurons, as well as the autonomic nervous system, which orchestrates basic body functions such as heartbeat, blood pressure, breathing and digestion.
It’s difficult to pinpoint whether some autism traits arise in the peripheral nervous system or the central nervous system; in many cases, complex feedback loops link the two. “Your nervous system doesn’t know that we’ve divided it that way,” says Carissa Cascio, associate professor of psychiatry and behavioral sciences at Vanderbilt University in Nashville, Tennessee.
But at least some peripheral changes may offer novel treatment targets. And drugs that act in the peripheral nervous system could also prove more effective and have fewer side effects than brain-based therapies, says Julia Dallman, associate professor of biology at the University of Miami in Coral Gables, Florida.
“I think there’s actually a lot of opportunities for peripherally targeted treatments,” says geneticist Lauren Orefice, assistant professor of genetics at Harvard Medical School and Massachusetts General Hospital. “It’s interesting because it is the opposite of what we’ve tried to do in neuroscience for a really long time” — that is, getting drugs into the brain.
This new focus on the periphery is already prompting fresh thoughts about old data, says Elisa Hill-Yardin, a neuroscientist at RMIT University in Melbourne, Australia. When she set out to investigate the role of autism-linked genes in the gut, for example, the NLGN-3 mouse was one of few autism mouse models available. When she discovered gut problems in the mice, she reached out to the doctors who had cared for the first children identified with NLGN-3 mutations.
“And lo and behold, those two boys, who are now adults in Sweden, both had really quite serious gastrointestinal dysfunction,” Hill-Yardin says. The details had “been beautifully recorded” by the doctors but went unmentioned in the report because they seemed irrelevant in characterizing an autism-related gene.
Here we take you on a quick tour of some of the different lines of evidence linking autism to the peripheral nervous system.
Touch receptors:
Many people with autism have unusual responses to touch. Some are hypersensitive to the slightest tap; some are soothed by the constant, all-over pressure of a weighted blanket.
Alterations to a diverse array of sensory receptors may drive such atypical responses. For example, mice lacking the autism-linked genes MECP2, GABRB3 or SHANK3 only in certain touch neurons are hypersensitive to puffs of air on their back, researchers led by David Ginty, professor of neurobiology at Harvard University, reported in 2016.
“When we deleted these genes in the peripheral sensory neurons, that essentially perfectly recapitulated the tactile hypersensitivity we observed in mice that had the genes deleted throughout the entire body, including the brain,” says Orefice, who conducted the work as a postdoctoral researcher in Ginty’s lab and is continuing the investigations in her own lab. By contrast, disrupting one of the genes, MECP2, only in a part of the brain responsible for processing sensory information did not alter the animals’ responses.
Research image of sensory neuron endings wrapping around hair follicles in a mouse’s skin.
On the surface: Mice missing autism-linked genes only in their peripheral sensory neurons, shown wrapped around hair follicles, have anxiety and other autism-like traits.
Mice missing the genes in touch receptors from birth also display anxiety and autism-like social differences, the team found. But if the genes are turned off in the touch receptors later in life, the animals have tactile hypersensitivity but not anxiety, and only mild social impairments.
“So, a deletion in the peripheral neuron is actually leading to changes in brain-driven behaviors,” Orefice says. The finding suggests that when peripheral nerves don’t function typically, it may change how social areas of the brain develop — and in so doing, drive some of autism’s core traits.
Drugs that dampen the activity of touch receptors can ease touch hypersensitivity, anxiety and some social deficits in six different mouse models of autism, Orefice and her colleagues showed in another study, raising the possibility that drugs that act in the peripheral nervous system might relieve sensory overload and perhaps other difficulties for people with autism.
spectrumnews.org
That’s starting to change. Although autism is typically thought of as a brain condition, a critical mass of researchers has started to investigate how the condition alters neurons elsewhere in the body. Their work — part of a broader trend in neuroscience to look beyond the brain — hints that the role of the peripheral nervous system in autism is, well, anything but peripheral: Neuronal alterations outside the brain may help to explain a host of the condition’s characteristic traits.
Much of the research so far focuses on touch and the workings of the gut, but there is increasing interest in other sensory and motor neurons, as well as the autonomic nervous system, which orchestrates basic body functions such as heartbeat, blood pressure, breathing and digestion.
It’s difficult to pinpoint whether some autism traits arise in the peripheral nervous system or the central nervous system; in many cases, complex feedback loops link the two. “Your nervous system doesn’t know that we’ve divided it that way,” says Carissa Cascio, associate professor of psychiatry and behavioral sciences at Vanderbilt University in Nashville, Tennessee.
But at least some peripheral changes may offer novel treatment targets. And drugs that act in the peripheral nervous system could also prove more effective and have fewer side effects than brain-based therapies, says Julia Dallman, associate professor of biology at the University of Miami in Coral Gables, Florida.
“I think there’s actually a lot of opportunities for peripherally targeted treatments,” says geneticist Lauren Orefice, assistant professor of genetics at Harvard Medical School and Massachusetts General Hospital. “It’s interesting because it is the opposite of what we’ve tried to do in neuroscience for a really long time” — that is, getting drugs into the brain.
This new focus on the periphery is already prompting fresh thoughts about old data, says Elisa Hill-Yardin, a neuroscientist at RMIT University in Melbourne, Australia. When she set out to investigate the role of autism-linked genes in the gut, for example, the NLGN-3 mouse was one of few autism mouse models available. When she discovered gut problems in the mice, she reached out to the doctors who had cared for the first children identified with NLGN-3 mutations.
“And lo and behold, those two boys, who are now adults in Sweden, both had really quite serious gastrointestinal dysfunction,” Hill-Yardin says. The details had “been beautifully recorded” by the doctors but went unmentioned in the report because they seemed irrelevant in characterizing an autism-related gene.
Here we take you on a quick tour of some of the different lines of evidence linking autism to the peripheral nervous system.
Touch receptors:
Many people with autism have unusual responses to touch. Some are hypersensitive to the slightest tap; some are soothed by the constant, all-over pressure of a weighted blanket.
Alterations to a diverse array of sensory receptors may drive such atypical responses. For example, mice lacking the autism-linked genes MECP2, GABRB3 or SHANK3 only in certain touch neurons are hypersensitive to puffs of air on their back, researchers led by David Ginty, professor of neurobiology at Harvard University, reported in 2016.
“When we deleted these genes in the peripheral sensory neurons, that essentially perfectly recapitulated the tactile hypersensitivity we observed in mice that had the genes deleted throughout the entire body, including the brain,” says Orefice, who conducted the work as a postdoctoral researcher in Ginty’s lab and is continuing the investigations in her own lab. By contrast, disrupting one of the genes, MECP2, only in a part of the brain responsible for processing sensory information did not alter the animals’ responses.
Research image of sensory neuron endings wrapping around hair follicles in a mouse’s skin.
On the surface: Mice missing autism-linked genes only in their peripheral sensory neurons, shown wrapped around hair follicles, have anxiety and other autism-like traits.
Mice missing the genes in touch receptors from birth also display anxiety and autism-like social differences, the team found. But if the genes are turned off in the touch receptors later in life, the animals have tactile hypersensitivity but not anxiety, and only mild social impairments.
“So, a deletion in the peripheral neuron is actually leading to changes in brain-driven behaviors,” Orefice says. The finding suggests that when peripheral nerves don’t function typically, it may change how social areas of the brain develop — and in so doing, drive some of autism’s core traits.
Drugs that dampen the activity of touch receptors can ease touch hypersensitivity, anxiety and some social deficits in six different mouse models of autism, Orefice and her colleagues showed in another study, raising the possibility that drugs that act in the peripheral nervous system might relieve sensory overload and perhaps other difficulties for people with autism.
spectrumnews.org