Neurons in human muscles emphasize stimulation from the outside world

Stretch sensors in our muscles participate in reflexes that serve the subconscious control of posture and movement. According to a new study published in the Journal of Neuroscience, these sensors respond weakly to muscle stretch caused by one’s voluntary action, and most strongly to stretch that is imposed by external forces. The ability to reflect causality in this manner can facilitate appropriate reflex control and accurate self-perception.  

“The results of the study show that stretch receptors in our muscles indicate more than which limb is moving or how fast; these sensors also adjust their signals according to who caused the movement,” says Michael Dimitriou, who conducted this study and is currently a post doc at the Department of Integrative Medical Biology, Umeå University, Sweden.

Normally, we can easily distinguish between movements we make ourselves and movements that are imposed on our body by external forces. The ability to discriminate between self-generated and externally generated sensory events is crucial for accurate perception and the control of posture and movement. This ability is also believed to form the foundation on which conscious self-awareness is built.

Such discrimination between self and other has previously been thought to arise as a result of complex computations performed in the brain, that use prior knowledge or memories of the consequences of own actions. But the study by Michael Dimitriou shows that information on the cause of a sensory effect can be provided in real-time by so-called ‘muscle spindles’, a class of stretch receptors found in most of our skeletal muscles.

Muscle spindles differ from other sensory receptors, such as stretch receptors in the skin, because their sensitivity can be controlled by the nervous system via specialized motor neurons. The purpose of this control has been unclear. The neural data presented by Michael Dimitriou indicates that these specialized motor neurons increase the sensitivity of stretch receptors when the body is exposed to an externally imposed stretch stimulus, such as when a falling ball is caught in the hand. Because amplified spindle responses mean stronger stretch reflexes, the resulting muscle activity instantly counteracts movement of the hand. When making a voluntary movement, however, the nervous system ‘automatically’ reduces the sensitivity of spindles in the stretching muscles, thereby making it possible for us to move without setting off strong stretch reflexes that would otherwise counteract movement. Uncontrollably strong stretch reflexes are commonly referred to as ‘spasticity’.

“These results provide an explanation of how reflexes can be functionally adjusted to help us achieve our everyday tasks, without requiring conscious control of reflex sensitivity or complex computations in the brain for predicting the sensory consequences of our actions,” says Michael Dimitriou.

He believes that these new findings are important both for understanding the neural mechanisms that underlie movement control and self-perception, but also for understanding pathological states where these mechanisms are disturbed.

“With these findings, we also get new insights into mechanisms whose malfunction may contribute to neuromuscular problems such as spasticity or alien hand syndrome (also known as ‘Dr. Strangelove syndrome’), and help identify potential treatment targets for these conditions,” says Michael Dimitriou.

Alzheimer’s disease protein controls movement in mice

Researchers in Berlin and Munich, Germany and Oxford, United Kingdom, have revealed that a protein well known for its role in Alzheimer’s disease controls spindle development in muscle and leads to impaired movement in mice when the protein is absent or treated with inhibitors. The results, which are published in The EMBO Journal, suggest that drugs under development to target the beta-secretase-1 protein, which may be potential treatments for Alzheimer’s disease, might produce unwanted side effects related to defective movement.

Alzheimer’s disease is the most common form of dementia found in older adults. The World Health Organization estimates that approximately 18 million people worldwide have Alzheimer’s disease. The number of people affected by the disease may increase to 34 million by 2025. Scientists know that the protein beta-secretase-1 or Bace1, a protease enzyme that breaks down proteins into smaller molecules, is involved in Alzheimer’s disease. Bace1 cleaves the amyloid precursor protein and generates the damaging Abeta peptides that accumulate as plaques in the brain leading to disease. Now scientists have revealed in more detail how Bace1 works.

"Our results show that mice that lack Bace1 proteins or are treated with inhibitors of the enzyme have difficulties in coordination and walking and also show reduced muscle strength," remarked Carmen Birchmeier, one of the authors of the paper, Professor at the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany, and an EMBO Member. "In addition, we were able to show that the combined activities of Bace1 and another protein, neuregulin-1 or Nrg1, are needed to sustain the muscle spindles in mice and to maintain motor coordination."

Muscle spindles are sensory organs that are found throughout the muscles of vertebrates. They are able to detect how muscles stretch and convey the perception of body position to the brain. The researchers used genetic analyses, biochemical studies and interference with pharmacological inhibitors to investigate how Bace1 works in mice. “If the signal strength of a specific form of neuregulin-1 known as IgNrg1 is gradually reduced, increasingly severe defects in the formation and maturation of muscle spindles are observed in mice. Furthermore, it appears that Bace1 is required for full IgNrg1 activity. The graded loss of IgNrg1 activity results in the animals having increasing difficulties with movement and coordination,” says Cyril Cheret, the first author of the work.

Drug developers are interested in stopping the Bace1 protein in its tracks because it represents a promising route to treat Alzheimer’s disease. If the protein were inhibited, it would interfere with the generation of the smaller damaging proteins that accumulate in the brain as amyloid plaques and would therefore provide some level of protection from the effects of the disease. “Our data indicate that one unwanted side effect of the long-term inhibition of Bace1 might be the disruption of muscle spindle formation and impairment of movement. This finding is relevant to scientists looking for ways to develop drugs that target the Bace1 protein and should be considered,” says Birchmeier. Several Bace1 inhibitors are currently being tested in phase II and phase III clinical trials for the treatment of Alzheimer’s disease.