Project Summary/Abstract
Prolonged social and environmental stress exposure tax the adaptive capacity (flexibility) of an individual
and is widely recognized as a major determinant of risk and severity of neuropsychiatric disease. Disorders
such as major depression disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia exhibit a
number of overlapping behavioral symptomologies, including impaired cognition, that are also observed with
chronic psychosocial stress1-3 . The range of cognitive problems is diverse, however the most consistently
documented deficits include impaired cognitive flexibility, inhibitory control, and working memory2,3. Impairments
in flexibility increase susceptibility to negative life events, reduce emotional control, and promote development
of maladaptive behaviors that disrupt abilities to engage effectively2,3. Despite the widespread repercussions of
intact flexibility, the neural substrates responsible for coincident processing involved in this behavior remain
unclear.
The prelimbic cortical region (PrLC) of the medial PFC encodes high order functions, including cognitive
flexibility using a complex framework of downstream glutamate projections to the nucleus accumbens (NAc) and
thalamic structures such as the mediodorsal thalamus (MDT) to guide behavior and detect and resolve conflicts
when rules change. Numerous studies have shown that stress-related psychopathology, including reduced
cognitive control is associated with synaptic and structural modifications in PrLC circuits. However, the specific
cortical output pathways that exhibit these adaptations and how they impact the function of these networks to
promote behavioral consequences of chronic stress are not well-defined. Our recently published findings indicate
that in the PrLC, CUS promotes opposing changes in intrinsic excitability, neuronal firing, and balance of
excitatatory:inhibitory synaptic regulation in pyramidal neurons (PN) expressing dopamine D1 vs. D2-type
receptors. Pilot data show that these opposing effects occur within D1-PN projecting to the NAc and D2-PN
projecting to the MDT. This exploratory proposal will build upon these findings by gaining insight into the
neuropathology that underlies these adaptations in terms of the source and anatomical selectivity of inhibitory
synaptic changes (Aim1) and identifying contributions of these sub-circuits to information processing related to
cognitive flexibility (Aim 2). We will use an operant-based model of attentional set-shifting (akin to the Wisconsin
Card Sorting Task) in transgenic Cre-mice combined with ex vivo optogenetic whole-cell recordings to assess
cell-type/pathway-specific plasticity and in vivo circuit-specific chemogenetics to identify how increasing or
decreasing activity of these circuits uniquely alters flexible decision-making.
