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Basal ganglia and sleep related motor disorders

Award Number: R01NS082242
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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Basal ganglia and sleep related motor disorders - DESCRIPTION (provided by applicant): Restless legs syndrome (RLS) and periodic leg movement (PLM) disorder, which produce one of the most profound variants of insomnia, affect 10% of the population and 32% of iron deficient (ID) anemia patients. Though dopaminergic drugs are effective in the treatment of RLS and PLM disorder, they are frequently only effective for short-term use. Augmentation of symptoms is often seen with long-term use. An animal model would greatly increase our understanding of RLS and PLM disorder, as has been the case for other disorders. Iron deficiency, which produces changes in dopaminergic neurons and receptors in the substantia nigra (SN) and putamen, has been reported to correlate with RLS. We hypothesize that GABAergic mechanisms in the SN may also play a critical role in the control of sleep and motor activity. We recently developed several animal models that exhibit sleep disorders similar to those seen in RLS patients. We found that neurotoxic NMDA lesions of the lateral ventral midbrain including the SN pars reticulata (SNR) produce hyposomnia with an increase in motor activity in slow wave sleep (SWS) in the cat. Our preliminary studies have shown that GABA levels in the SNR are positively correlated with wake time in the rat. We also found in our preliminary studies that muscimol, a GABAA receptor agonist, infused into the SNR decreases sleep and induces PLM in quiet wakefulness and SWS in the rat. Our preliminary study showed that rats with neurotoxic lesions of the putamen, which projects to the SNR via the globus pallidus, also exhibit hyposomnia and PLM in quiet wake and in sleep. In addition, our preliminary data showed that ID rats have insomnia and severe PLM in wake and in SWS. The sleep pattern and symptoms of putamen-lesioned rats and ID rats resemble human RLS patients. Our preliminary data showed that systemic injection of dopamine agonist suppresses PLM in putamen-lesioned and ID rats, similar to humans. These indicate that both putamen-lesioned and ID rats would serve as ideal animal models of primary and secondary RLS. We found that the sleep disturbances in ID rats can be improved by iron replacement (IR). We also found in our preliminary study that histamine H3 receptor (H3R) mechanisms play a role in the control of sleep-related motor activity. Systemic administration of a H3R antagonist effectively suppressed PLM in wake and in sleep, in both putamen-lesioned and ID rats. We found in our preliminary study that striatal levels of H3R are high in ID and low in normal and IR animals. We propose to determine the role that GABAergic and histaminergic mechanisms play in the regulation of sleep and motor activity, through the use of neurotoxic lesion, in vivo microdialysis HPLC analysis, microinfusion of GABAA receptor agonists and antagonists, systemic injection of H3R agonist and antagonist, Western blotting, and EEG spectral analysis techniques.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	SEPULVEDA RESEARCH CORP	16111 PLUMMER ST STE 111	NORTH HILLS	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	SEPULVEDA RESEARCH CORP	16111 PLUMMER ST STE 111	NORTH HILLS	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	SEPULVEDA RESEARCH CORP	16111 PLUMMER ST STE 111	NORTH HILLS	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $284,594 )
2018	2018	SEPULVEDA RESEARCH CORP	16111 PLUMMER ST STE 111	NORTH HILLS	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/29/2018	NON-COMPETING CONTINUATION	$284,594
														Subtotal = $284,594

Issue Date FY: 2017 ( Subtotal = $284,594 )
2017	2017	SEPULVEDA RESEARCH CORP	16111 PLUMMER ST STE 111	NORTH HILLS	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	6/13/2017	NON-COMPETING CONTINUATION	$28,460
2017	2017	SEPULVEDA RESEARCH CORP	16111 PLUMMER ST STE 111	NORTH HILLS	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/13/2017	NON-COMPETING CONTINUATION	$256,134
														Subtotal = $284,594

Issue Date FY: 2016 ( Subtotal = $284,594 )
2016	2016	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/29/2016	NON-COMPETING CONTINUATION	$284,594
														Subtotal = $284,594

Issue Date FY: 2015 ( Subtotal = $384,594 )
2015	2015	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/24/2015	SUPPLEMENT FOR EXPANSION	$100,000
2015	2015	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/7/2015	NON-COMPETING CONTINUATION	$284,594
														Subtotal = $384,594

Issue Date FY: 2014 ( Subtotal = $284,594 )
2014	2014	SEPULVEDA RESEARCH CORPORATION	16111 PLUMMER STREET	SEPULVEDA	CA	91343	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/5/2014	NEW	$284,594
														Subtotal = $284,594

Grand Total All Awards = $1,522,970

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Basal ganglia and sleep related motor disorders

Award Number: R01NS082242

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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