Methamphetamine Effects on Prefrontal Cortical PV+ Interneurons and Resulting Cognitive Deficits

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SUMMARY This Diversity Supplement support is for Dr. Monserrat Armenta-Resendiz in the laboratory of Dr Antonieta Lavin at the Medical University of South Carolina with additional mentorship by Dr. Carmela Reichel and Tom Jhou. Dr. Armenta-Resendiz is a Latina woman whose goal is to become an independent scientist in a field that will intersect drug addiction, cognitive deficits and sex differences. Dr Armenta-Resendiz needs to acquire additional technical skills, enhance her professional skills, and develop an academic profile to ensure she is in a competitive position to apply for R type founding and tenure track academic positions. The objective of the parent R01 (DA 054589-01) is is to identify the effects of METH-SA on the activity of cortical parvalbumin positive fast spiking interneurons (PV+FSIs) and the resulting changes in E-I ratio. The central hypothesis- informed by strong preliminary data and literature- is that METH treatment elicits cognitive deficits due to an increase in GABAergic synaptic transmission in the PFC via D1R activation of PV+FSIs. The proposal’s rationale is that the experiments will yield fundamental knowledge pertaining to the understanding of the cellular and synaptic mechanisms underlying hypofrontality induced by METH and will provide new insights into the basic mechanisms governing E-I balance in the prefrontal cortex. We will test the central hypothesis by pursuing the following specific aims: Aim 1 will determine the role of PV+FSIs in METH-induced cognitive deficits. Aim 2 will determine whether D1R signaling in PFC PV+FSIs is required for METH-induced enhancements of GABAergic transmission. Aim 3 will determine whether D1R signaling in PFC PV+FSIs is required for METH SA-induced cognitive deficits and METH reinstatement. The proposed research is significant because it will fill a fundamental gap in knowledge pertaining to the mechanisms underlying hypofrontality in METH-addiction and the effects of the psychostimulant in the activity of cortical PV+FSIs. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate drug- related cognitive deficits and can provide new insights into the basic mechanisms underlying hypofrontality in other neuropsychiatric conditions. To support the training of Dr Armenta-Resendiz, we have developed an additional aim that extends and complements the parent RO1. 1. She will implement fiber photometry assessments of DA and Glutamate sensors in the PFC of METH and SAL male and female rats during the performance of a cognitive task (Temporal Order Memory) in vivo. This training program will provide Dr Armenta-Resendiz with additional skills in fiber photometry, sex defenses and behavior. She will also receive additional mentorship from a diverse team and trainings to ensure she is fully equipped for her chosen career path.