PROJECT SUMMARY Hypofrontality corresponds to a state of reduced frontal cortex activity found in several neuropsychiatric disorders, including substance use disorders and depression, that correlates with cognition and executive function disabilities. However, the mechanisms underlying hypofrontality development in response to experience remain unknown. Perineuronal nets (PNNs) are composed of extracellular matrix glycoproteins, are dysregulated in drug addiction and depression, and have emerged as important regulators of synaptic plasticity in the developing and mature brain. PNNs formation around parvalbumin-positive fast spiking interneurons (PV+FSIs) tends to increase PV+FSIs activity, which enhances GABAergic inhibition in neuronal networks and suggests the potential involvement of PNNs in hypofrontality. Our preliminary data, using a rat model of prefrontal cortex (PFC) hypofunction (i.e. hypofrontality) induced by chronic methamphetamine (METH) administration, suggest that chronic METH induces an increase in the percentage of PV+FSIs surrounded by PNNs, associated with an increase in PV+FSIs excitability, an increase in inhibitory transmission onto pyramidal neurons, as well as the emergence of cognitive deficits. The overall objective of this proposal is to study the role of PNNs in METH-induced hypofrontality and cognitive deficits. The central hypothesis- informed by strong preliminary data and literature- is that METH-induced increase in PNNs enhances PV+FSIs activity in the PFC and produces hypofrontality and cognitive deficits. Aim 1 will assess when chronic METH self-admnistration initaites changes in PNNs density, expression level and compostion and whether these changes are long-lasting. Aim 2 will investigate the role of PNNs in METH- induced cognitive deficits. Aim 3 will assess the role of PNNs in METH-induced hypofrontality. The proposed research is significant because it will fill fundamental gap in knowledge related to the mechanisms underlying hypofrontality in METH-addiction. The main conceptual innovation of the proposed study is the investigation of the link between PNNs and hypofrontality. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate hypofrontality-related symptoms in SUD and other psychiatric conditions and can also provide new insights into the basic mechanisms underlying hypofrontality.