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Chemogenetic afferent modulation to understand spinal cord circuit function and plasticity post injury

Award Number: R01NS114007
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Chemogenetic afferent modulation to understand spinal cord circuit function and plasticity post injury - PROJECT SUMMARY Spinal cord injury (SCI) causes life-long neurological impairment, and there is currently no effective treatment. The premise of this proposal is recent work demonstrating that afferent stimulation paired with treadmill training can enhance standing, stepping, and volitional control in humans and animal models. Therefore, it is critically important to understand the mechanisms by which afferent stimulation drives motor improvement. Tools that can identify which afferents are necessary and sufficient to enhance recovery, and that can facilitate characterization of the helpful neural plasticity, are urgently needed. Our long-term goal is to develop approaches for selective afferent modulation, and apply them to the dissection of the mechanisms underlying recovery from SCI. The objective of this grant is to identify which sets of afferents are important for recovery and how spinal circuits change to facilitate it. To achieve selective modulation of afferents and enable genetic tracing we will use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that can modulate excitability in specific populations of neurons. To accurately quantify improvement, we will use Deep Learning to analyze large kinematic data sets. Our preliminary data shows strong expression of DREADDs in large diameter DRG neurons, that their activation by CNO can excite or inhibit the H-reflex, and that activation of excitatory DREADDs during treadmill training post-SCI improves stepping. Our main hypothesis is that activation of large afferents by the excitatory DREADD (hM3Dq) during treadmill training will enhance recovery, whereas inhibitory DREADDs (hM4Di) will suppress recovery. Four sub- hypotheses will test whether recovery is mediated by increased afferent projection onto 1) motor neurons, or 2) inhibitory interneurons; or by sprouting of 3) reticulospinal and 4) propriospinal circuits. Our Specific Aims are to determine whether selective expression of DREADDs in (Aim 1) all large diameter (proprioceptive and tactile) neurons and (Aim 2) large proprioceptive afferents only can enhance recovery. The rationale for these aims is that afferent stimulation is hypothesized to work through selective excitation of large diameter sensory afferents (LDSA) that both drive motor pools locally and facilitate proprio- and surpraspinal input. To date, it has not been possible to definitively determine which afferents were recruited after electrical stimulation, or to select between afferents of similar diameter. The significance of this work lies in determining whether recovery is mediated exclusively by proprioceptive axons or a combination of proprioceptive and tactile afferents, and uncovering the mechanisms of functional plasticity in the spinal cord.


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 = $374,900 )
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/22/2024	NON-COMPETING CONTINUATION	$374,900
														Subtotal = $374,900

Issue Date FY: 2023 ( Subtotal = $390,183 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/7/2023	NON-COMPETING CONTINUATION	$390,183
														Subtotal = $390,183

Issue Date FY: 2022 ( Subtotal = $391,984 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/24/2022	NON-COMPETING CONTINUATION	$391,984
														Subtotal = $391,984

Issue Date FY: 2021 ( Subtotal = $395,672 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/10/2021	NON-COMPETING CONTINUATION	$395,672
														Subtotal = $395,672

Issue Date FY: 2020 ( Subtotal = $416,293 )
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/18/2020	NEW	$416,293
														Subtotal = $416,293

Grand Total All Awards = $1,969,032

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Chemogenetic afferent modulation to understand spinal cord circuit function and plasticity post injury

Award Number: R01NS114007

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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