by University of California, Irvine
Selective cilia deletion in the striatum and confirmation of mice’s normal gross growth and well-being. a Schematic view of experimental design and behavior assays performed and their sequence. Diagram was created with the BioRender.com webpage. b Schematic showing bilateral viral injection into the dorsal striatum. c and d Verification of cilia removal in ciliated neurons of the striatum using immunostaining of ADCY3. Scale bar = 10 μm. c Representative images of ADCY3 immunostaining showing the intact cilia in the control mice and the conditional ablation of cilia in the dorsal striatum neurons of Ift88fl mice (counterstained with DAPI, blue); d Quantification of the ciliated cells in the rostral-dorsal striatum (n = 8 control, 6 IFT88-KO). Unpaired t-test (t = 17.26, P is less than 0.0001) ****P < 0.0001. Data are presented as means ± S.E.M. Scale bar = 10 μm. e–g ADCY3 immunostaining in the caudal striatum. e Representative images of ADCY3 immunostaining in the caudal striatum showing that the selective removal of cilia from the dorsal rostral striatum does not affect f the number of ciliated cells (t = 0.30, P is greater than 0.05) or g the cilia length (t = 0.30, P is greater than 0.05, n = 4) in the caudal striatum. Scale bar = 10 μm. h–j ADCY3 immunostaining in the ventral striatum (nucleus accumbens). h Representative images of ADCY3 immunostaining in the ventral striatum showing that the selective removal of cilia from the rostral striatum does not affect i the number of ciliated neurons (t = 0.52, P is greater than 0.05) or j the cilia length (t = 0.08, P is greater than 0.05, n = 4) in the ventral striatum. Scale bar = 10 μm. k Effect of cilia removal on body weight to confirm normal gross growth (n = 8 control, 6 IFT88-KO). Unpaired t-test (t = 0.2463, P = 0.8096) revealed no significant difference in body weight. ns, not significant. Data are presented as means ± S.E.M. l Verification of well-being (n = 8 control, 6 IFT88-KO). Unpaired t-test (t = 0.2060, P = 0.8403) showed normal response to nociceptive stimulus. ns, not significant. Data are presented as means ± S.E.M. Credit: Molecular Neurobiology (2022). DOI: 10.1007/s12035-022-03095-9
Researchers at the University of California, Irvine have discovered that removal of cilia from the brain’s striatum region impaired time perception and judgment, revealing possible new therapeutic targets for mental and neurological conditions including schizophrenia, Parkinson’s and Huntington’s diseases, autism spectrum disorder, and Tourette syndrome.
The striatum processes and integrates new environmental sensory information and coordinates the time sequence of motor responses. A common feature across specific mental and neurological disorders is a profound decline in patients’ ability to adjust to variations in their surroundings and accurately estimate the timing and termination of voluntary actions.
The study, recently published online in the journal Molecular Neurobiology, uncovered the first evidence of the important role cilia play in timing-dependent dysfunction.
“Our findings may revolutionize our understanding of brain functions and mental disorders in the context of the critical task performed by these previously unappreciated organelles in the brain’s ‘central clock’ function,” said Amal Alachkar, Ph.D., corresponding author and professor of teaching in UCI’s Department of Pharmaceutical Sciences. “Our results may open new avenues for effective intervention through cilia-targeted therapies for treatment.”
The striatum is part of the brain’s circuitry that performs central clock processes, essential in controlling executive functions such as motor coordination, learning, planning and decision-making, as well as working memory and attention. Cilia protrude from the brain cell surfaces like antennae, working as a signaling hub that senses and transmits signals to generate appropriate reactions.
To examine their physiological role, the researchers removed cilia from the striatum in mice using conditional gene manipulation technology. These rodents were not able to learn new motor tasks, showed repetitive motor behavior and exhibited delays in decision-making. They were also deficient in rapidly recalling information about their location and orientation in space and in their ability to filter irrelevant environmental sensory information. However, the mice maintained habitual or already learned motor skills and long-term memories.
“Successful performance of working memory, attention, decision-making and executive function requires accurate and precise timing judgment, usually within a millisecond to a minute,” Alachkar said. “When that capacity is impaired, it means losing the ability to quickly adjust behavior in response to changes in external stimuli and failing to sustain appropriate, goal-oriented motor responses. Our ongoing work is aimed at understanding the mechanisms by which cilia regulate time perception and developing targeted therapies to improve behavioral deficits.”
Team members also included pharmaceutical sciences graduate students Wedad Alhassen, Sammy Alhassen, Kiki Jiaqi Chen and Roudabeh Vakil Monfared.
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