ABSTRACT
Autism spectrum disorder (ASD) is a human neurodevelopmental condition that features deficits in
affiliation/attachment behavior and early life sleep. Prairie voles (Microtus ochrogaster) are a wild rodent
species that are an ideal animal model in which to study affiliation/attachment (an RDoC domain), since unlike
traditional lab rats and mice, they display strong affiliation with opposite-sex mates. Variation in medial
prefrontal cortex (mPFC) structure predicts differences in affiliation/attachment behavior, both across and
within vole species. Additionally, the mPFC-NAcc (nucleus accumbens) network is both necessary and
sufficient for social bond formation in prairie voles. Moreover, mPFC and mPFC-NAcc have been implicated in
both ASD1,2 and neurotypical human attachment. However, exactly how mPFC-NAcc network dysregulation
occurs during the course of brain development, and what form this takes at the cellular level, is still unknown.
Due to the late maturation of the mPFC, affiliation/attachment may be particularly vulnerable to postnatal
events such as sleep disruption and we reported that early life sleep disruption (ELSD) in prairie vole pups in
the 3rd postnatal week led to a combination of reduced affiliation/attachment later in life and increases in mPFC
dendritic spines. This mirrors the combination of early-life sleep disruption, mPFC network changes, and
reductions in affiliation/attachment behavior in humans with ASD. However, despite our recent findings, two
major knowledge gaps remain: 1) How ELSD affects the longitudinal development of affiliation/attachment, and
how early changes may predict adult phenotypes, and 2) How the mPFC network functional state is altered,
with a specific knowledge gap related to effects on E/I balance. We hypothesize that the mPFC changes in
ELSD will result in alterations in both the developmental trajectory of affiliation/attachment and mPFC
electrophysiological activity, and ELSD-induced social deficits will be rescued by optogenetic stimulation of
mPFC-NAcc projections at theta frequencies. We will test these hypotheses by pursuing 3 aims: Aim 1:
Determine effects of early life sleep disruption (ELSD) on the longitudinal development of affiliation/attachment
using continuous, high-resolution, high-throughput behavioral phenotyping. Aim 2: Determine the effects of
ELSD on mPFC electrophysiological state during affiliation/ attachment behaviors. Aim 3: Manipulate mPFC to
NAcc projection activity to rescue ELSD-induced deficits in affiliation/ attachment behaviors. We hypothesize
that theta-frequency stimulation of mPFC-NAcc will rescue affiliation/attachment deficits in ELSD voles. These
experiments will greatly expand our knowledge of the ELSD model of social deficits. They also directly test the
rescue of behavioral deficits using mPFC optogenetic stimulation to generate a new intervention. Future work
can build on this foundation by intervening during developmental to alter life-long trajectories in social
affiliation-attachment using sleep, molecular, and network-level approaches.
