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Compartmental, rhythmic and plastic neuropeptide release

Award Number: R01NS032385
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: 08/04/1995
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Compartmental, rhythmic and plastic neuropeptide release - Neuropeptides are crucial in development and for a wide variety of behaviors including circadian rhythms and sleep. This project has been using imaging to study synaptic neuropeptide release. For example, a new optical method based on a fluorogen activating protein (FAP) has shown that activity-evoked synaptic neuropeptide release occurs solely via fusion pores formed by kiss and run exocytosis. These experiments also established that synaptic fusion pores open spontaneously at a low rate, thereby providing a basis for resting peptidergic transmission. Furthermore, FAP imaging in the brain showed that Drosophila clock neurons release neuropeptides daily with different rhythms from terminals and the soma. This differential timing is based on the use of independent triggers: synaptic release requires Ca2+ influx as expected for release induced by electrical activity, but somatic release is mediated by the biochemical signal IP3. Remarkably, perturbing the somatic release mechanism alters specific features of circadian behavior and sleep. Thus, spatially and temporally partitioned neuropeptide release controls rhythmic behaviors. In parallel, GFP-tagged neuropeptide imaging led to the discovery of regulation of neuropeptide packaging by tyrosine phosphatases and new insights into neuropeptide delivery, capture and release at synapses. Finally, G-protein coupled receptor GPCR activation- based (GRAB) fluorescence sensors have been incorporated into our research to provide a new approach for resolving release and the subsequent spread of neuropeptides in the brain. Here the above optical tools will be used with Drosophila genetics to answer three questions posed by prior work on this project: (a) How is daily IP3 signaling induced in clock neurons and coupled to somatic neuropeptide release and regulation of rhythmic behaviors? (b) How does multi-compartmental fusion pore opening and dilation orchestrate neuropeptide release at native release sites? (c) How are neuropeptide packaging, axonal transport and synaptic capture controlled to support neuropeptide stores in release sites undergoing morphological plasticity (i.e., as occurs daily in clock neurons and in motor neuron axonal arbors in response to retrograde signaling)? These studies will reveal how surprising signaling-induced neuropeptide release from the soma participates the peptidergic connectome. Furthermore, in vivo imaging will elucidate the process of neuropeptide release by fusion pores. Finally, the cell biology underlying the support of peptidergic transmission during plasticity will be determined for the first time. Thus, this project will yield fundamental insights into neuropeptide release and the control of behavior, which are critical to the operation of the nervous system.


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: 2024 ( Subtotal = $772,484 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	28	7/18/2024	NON-COMPETING CONTINUATION	$772,484
														Subtotal = $772,484

Issue Date FY: 2023 ( Subtotal = $796,375 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	27	6/9/2023	NON-COMPETING CONTINUATION	$796,375
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	26	6/7/2023	COMPETING CONTINUATION	$257,027
2023	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	6/7/2023	NON-COMPETING CONTINUATION	-$257,027
														Subtotal = $796,375

Issue Date FY: 2022 ( Subtotal = $811,125 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	26	7/14/2022	COMPETING CONTINUATION	$797,118
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	26	8/26/2022	COMPETING CONTINUATION	$14,007
2022	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	7/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $811,125

Issue Date FY: 2021 ( Subtotal = $540,865 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	5/24/2021	NON-COMPETING CONTINUATION	$540,865
														Subtotal = $540,865

Issue Date FY: 2020 ( Subtotal = $542,813 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	5/8/2020	NON-COMPETING CONTINUATION	$542,813
														Subtotal = $542,813

Issue Date FY: 2019 ( Subtotal = $540,865 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	5/6/2019	NON-COMPETING CONTINUATION	$540,865
														Subtotal = $540,865

Issue Date FY: 2018 ( Subtotal = $541,951 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	5/1/2018	NON-COMPETING CONTINUATION	$541,951
														Subtotal = $541,951

Issue Date FY: 2017 ( Subtotal = $550,825 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	3/27/2017	COMPETING CONTINUATION	$550,825
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	21	8/21/2017	COMPETING CONTINUATION	$83,953
2017	2016	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	8/21/2017	EXTENSION WITH OR WITHOUT FUNDS	-$83,953
														Subtotal = $550,825

Issue Date FY: 2016 ( Subtotal = $389,605 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	5/13/2016	EXTENSION WITH OR WITHOUT FUNDS	$389,605
														Subtotal = $389,605

Issue Date FY: 2015 ( Subtotal = $389,605 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	4/21/2015	NON-COMPETING CONTINUATION	$389,605
														Subtotal = $389,605

Issue Date FY: 2014 ( Subtotal = $385,709 )
2014	2014	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	4/14/2014	NON-COMPETING CONTINUATION	$385,709
														Subtotal = $385,709

Issue Date FY: 2013 ( Subtotal = $375,968 )
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	5/22/2013	NON-COMPETING CONTINUATION	$25,324
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	4/26/2013	NON-COMPETING CONTINUATION	$350,644
														Subtotal = $375,968

Issue Date FY: 2012 ( Subtotal = $402,480 )
2012	2012	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	5/18/2012	COMPETING CONTINUATION	$402,480
														Subtotal = $402,480

Issue Date FY: 2011 ( Subtotal = $417,421 )
2011	2011	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	4/15/2011	NON-COMPETING CONTINUATION	$390,859
2011	2011	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	7/11/2011	NON-COMPETING CONTINUATION	$26,562
														Subtotal = $417,421

Issue Date FY: 2010 ( Subtotal = $440,149 )
2010	2010	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	9/17/2010	SUPPLEMENT FOR EXPANSION	$22,725
2010	2010	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	4/30/2010	NON-COMPETING CONTINUATION	$417,424
														Subtotal = $440,149

Issue Date FY: 2009 ( Subtotal = $409,358 )
2009	2009	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	5/6/2009	NON-COMPETING CONTINUATION	$409,358
														Subtotal = $409,358

Issue Date FY: 2008 ( Subtotal = $421,312 )
2008	2008	UNIVERSITY OF PITTSBURGH	3017 CATHEDRAL OF LEARNING	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	4/2/2008	COMPETING CONTINUATION	$421,312
														Subtotal = $421,312

Issue Date FY: 2007 ( Subtotal = $350,387 )
2007	2007	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	5/10/2007	NON-COMPETING CONTINUATION	$350,387
														Subtotal = $350,387

Issue Date FY: 2006 ( Subtotal = $350,344 )
2006	2006	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/19/2006	NON-COMPETING CONTINUATION	$350,344
														Subtotal = $350,344

Issue Date FY: 2005 ( Subtotal = $353,397 )
2005	2005	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/19/2005	NON-COMPETING CONTINUATION	$353,397
														Subtotal = $353,397

Issue Date FY: 2004 ( Subtotal = $382,356 ) (Continued on the next page)
Grand Total All Awards = $11,395,060

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Compartmental, rhythmic and plastic neuropeptide release

Award Number: R01NS032385

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: 08/04/1995

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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