Friday, June 6, 2025
6/6/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).