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Developmental Biology - Inner ear balance|
Lopsided ear function can lead to a lopsided brain
In mice, left-right differences in ear function are now identified as leading to asymmetric brain development affecting their preferred direction when turning.
Motor asymmetry is the preferential use of a limb or a body part on one side of the body. Preference for use of either one hand or foot are commonly seen examples. But, despite a long fascination with asymmetries in left-right brain function by both public and science, very little is known about what causes functional brain asymmetry.
In a multi-national study publishing March 13th in the open access journal PLOS Biology, Michelle Antoine, Jean Hébert, and their colleagues at the Albert Einstein College of Medicine investigated the potential links between atypical asymmetry in motor behavior to defects in inner ear function.
The authors used mice with a genetic defect that affects their vestibular — balance — function of their inner ear. These mice tend to "circle" repetitively, with a preferred turning direction varying between individuals. Based on a series of genetic, surgical, and pharmacological experiments, researchers showed that even a short-term imbalance of inner ear function can lead to long-lasting brain asymmetry. It appears that levels of two key brain neurotransmitters are at fault - glutamate and dopamine.
Asymmetry between levels of glutamate and dopamine correlates with an animal's preferred turning direction. The motor-dominant hemisphere had higher levels of glutamate and lower levels of dopamine signals. Furthermore, researchers could manipulate glutamate and dopamine levels using an antagonist called ERK - Extracellular signal Regulated Kinase — to integrate both neurotransmitters to reduce, or even reverse, a preferred turning direction.
The authors also showed their findings extended to humans. Human subjects who underwent brain imaging while receiving stimulation to both ears, showed their ear with the weakest sense of balance correlated to the brain hemisphere linked to their preferred hand.
Functional brain asymmetry arises independent of other anatomical asymmetry — such as the position of the heart or liver. Why is unknown. However, showing asymmetry in sensory input from the ear can permanently affect asymmetric brain function, is an important insight into potential causal relationships.
How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear–induced striatal asymmetries identified here intersect with non–ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left–right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.
Despite a long-standing fascination with asymmetries in left–right brain function, very little is known about the causes of functional brain asymmetry in mammals, which appear independent of the mechanisms that create anatomical asymmetries during development. Asymmetries in motor function are a common example and include preferred turning direction, handedness, and footedness. In this study, using mouse models, we establish a causal link between transient imbalances in degenerating inner ear function and the establishment of stable asymmetries in neural pathways that regulate motor activity and in motor behavior. Our study also suggests that shared mechanisms may underlie lateralized motor behaviors across mammalian species. For example, we show that in humans with normal ear function, the strength of the vestibular response from each ear in the forebrain correlates with asymmetric motor behavior, measured as handedness. In a broader sense, our study reveals a conceptually novel role for sensory input in shaping the asymmetric distribution of brain function, a process for which there is otherwise no clear mechanism.
Authors: Michelle W. Antoine, Xiaoxia Zhu, Marianne Dieterich, Thomas Brandt, Sarath Vijayakumar, Nicholas McKeehan, Joseph C. Arezzo, R. Suzanne Zukin, David A. Borkholder, Sherri M. Jones, Robert D. Frisina, Jean M. Hébert.
Competing Interests: The authors have declared that no competing interests exist.
Funding: German Federal Ministry of Education and Research (grant number 01 EO 0901). Received by Marianne Dieterich, Thomas Brandt. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number AG009524). Received by Robert D Frisina. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. German Foundation for Neurology. Received by Marianne Dieterich. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Miller Institute for Basic Research in Science. Received by Michelle Antoine. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number MH083804). Received by Jean M Hébert. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Hertie-Foundation. Received by Thomas Brandt. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number HD090260). Received by Jean M Hébert. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number NS088943). Received by Jean M Hébert. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Fig 7. Imbalanced inner ear dysfunction determines preferred turning direction.
(D) Model of ear-induced lateralization.
Image credit: Michelle Antoine, Jean Hébert, Albert Einstein College of Medicine.