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Mechanisms of mGlu1 regulation of cortical inhibition and cognitive function: Implications in adolescent cocaine exposure

Award Number: K99DA058712
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Mechanisms of mGlu1 regulation of cortical inhibition and cognitive function: Implications in adolescent cocaine exposure - PROJECT SUMMARY/ABSTRACT Evidence suggests that cocaine use, notably during critical neurodevelopmental periods like adolescence, is associated with significant and persistent impairments in cognitive processes like working memory and cognitive flexibility. Cognitive symptoms are associated with loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC). Our preliminary data demonstrates that adolescent cocaine exposure induces persistent deficits in GABAergic somatostatin-expressing interneurons (SST-INs) in the PFC and cognitive performance in adulthood. Thus, enhancing cortical inhibition represents a novel therapeutic approach to alleviate cognitive deficits associated with adolescent cocaine exposure and cocaine use disorder (CUD). This therapeutic goal may be achieved via activation of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor. Leveraging highly selective mGlu1 positive allosteric modulators (PAMs), we recently found that mGlu1 positively regulates cortical inhibition via actions on SST-INs and improves cognitive performance. These findings led us to our central hypothesis that the ability of mGlu1 PAMs to reverse deficits in cortical inhibition and cognitive impairment associated with adolescent cocaine exposure is likely driven by actions on mGlu1 receptors located on SST-INs in the PFC. The present proposal will use cutting-edge transgenic mouse lines and pharmacological tools to elucidate brain region- and cell type-specific mechanisms underlying mGlu1 regulation of cortical inhibition and cognitive function and their implications following adolescent cocaine exposure. We will test this hypothesis in three specific aims. Aim 1 (K99): To gain expertise in whole-cell patch-clamp electrophysiology to test the hypothesis that mGlu1 regulates PFC inhibitory transmission via actions on SST-INs. Aim 2 (K99): To develop expertise in in vivo fiber photometry to test the hypothesis that mGlu1-mediated activation of PFC SST-INs facilitates working memory performance. Aim 3 (R00): To apply whole-cell patch-clamp electrophysiology and in vivo fiber photometry to test the hypothesis that mGlu1 modulation can ameliorate adolescent cocaine-induced pathophysiology through actions on PFC SST-INs. Together, the proposed studies will expand our current understanding of the critical role of SST-INs in cognitive processes impaired by adolescent cocaine use and evaluate the therapeutic potential of mGlu1 PAMs in mitigating these cocaine-induced deficits. I will gain extensive training in whole-cell patch-clamp electrophysiology and in vivo cell type-specific Ca2+ imaging during touchscreen-based cognitive testing. Training in these techniques will allow me to apply my interests in behavioral and receptor pharmacology to unanswered questions about how drug exposure during critical neurodevelopmental periods manifest in physiological and behavioral consequences of substance use disorders.


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: 2025 ( Subtotal = $144,235 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Drug Use and Addiction Research Programs	000	2	3/6/2025	NON-COMPETING CONTINUATION	$144,235
														Subtotal = $144,235

Issue Date FY: 2024 ( Subtotal = $144,235 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Drug Use and Addiction Research Programs	000	1	3/8/2024	NEW	$144,235
														Subtotal = $144,235

Grand Total All Awards = $288,470

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Mechanisms of mGlu1 regulation of cortical inhibition and cognitive function: Implications in adolescent cocaine exposure

Award Number: K99DA058712

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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