Project Summary
Adolescence is a time of extensive neural reorganization, especially in the prefrontal cortex of both humans
and rodents. One of the major changes that occurs in the medial prefrontal cortex is an increase in
perineuronal nets (PNNs), an extracellular matrix that preferentially surrounds parvalbumin (PV)-expressing
inhibitory interneurons, adding stability and functional support. Our recent data showed that female rats have a
decrease in PNNs at puberty, which males do not, and this may result in greater female vulnerability to drug
exposure during adolescence and at puberty. The premise of the current proposal is that the process of neural
maturation of fast-spiking, inhibitory PV interneurons, and the formation of PNNs and their components in the
medial prefrontal cortex, is an essential part of the vulnerability to substance use disorder during adolescence.
This will be tested with exposure to a highly abused drug, methamphetamine (METH). Aim 1 will determine
the short-term effects of METH exposure on both number and intensity of PV neurons and PNNs when
administered at three separate time points: early-adolescence (overlapping with female puberty), late-
adolescence (male puberty), or young adulthood. PV neurons, PNNs and their chondroitin sulfate
proteoglycan components will be quantified immediately with the pubertal status noted. We hypothesize that
there will be decreases in both PV intensity, the number of PNNs and their components, in the medial
prefrontal of the adolescent-exposed, compared to an increase in the young adult-exposed. This effect would
be indicative of the increased plasticity and resulting vulnerability to METH exposure in adolescence. We
predict females in the young adolescent, pubertal group will be the most affected. Aim 2 will test animals that
have been exposed to METH in Aim 1 and then are trained to self-administer METH as adults, followed by
assessment of PV neurons, PNNs and their components. We predict that groups that were previously exposed
as adolescents will exhibit greater escalation of intake and heightened motivation for METH that will be
associated with greater increases in PNN expression, with the early adolescent-exposed females being most
affected. The studies outlined here provide new avenues for future research on the impact of drug exposure
during adolescence and its effects on the structure of the mPFC and later behavior, which in turn may inform
the development of new treatment strategies.