Impact of social environment on cognitive development and thalamocortical maturation

PROJECT SUMMARY/ABSTRACT
Social interaction is essential to the cognitive development and wellbeing of many species including
humans. Social withdrawal is an early risk factor and predictor of mental illness onset and often begins during
adolescence. Adolescence is a period of increased plasticity during which environmental input and brain activity
guide circuitry maturation, including thalamo-prefrontal circuitry. Adolescent social interaction is necessary for
the establishment of adult cognitive behaviors, which rely on the prefrontal cortex (PFC). Our lab has previously
shown that adolescent inhibition of the medial thalamus (mTH) impairs PFC maturation and development of adult
cognitive flexibility in mice. I have observed that adolescent social isolation (ASI) impairs cognitive flexibility
selectively in females, who have been traditionally understudied in this field. Therefore, I hypothesize that ASI
induces cognitive impairments by reducing adolescent mTH activity and thalamo-prefrontal connectivity in a
sexually dimorphic manner. Furthermore, I have observed that some ASI-treated individuals do not show deficits
in cognitive flexibility. Indeed, many studies of ASI and other stressful paradigms have reported large variability
in behavioral adaptations, but little work has been done to uncover the underlying mechanisms of this variation.
I hypothesize that variation in the level of mTh activity and connectivity deficits will explain behavioral variation,
with higher activity and connectivity conferring resilience to ASI-induced cognitive deficits. With this in mind, I
have designed my study with the statistical power to detect sex differences and resilience.
I propose two periods for intervention to rescue and prevent ASI-induced cognitive deficits. Our lab has
shown that excitation of the mTH in adulthood transiently rescues cognitive flexibility in mice who underwent
adolescent mTH inhibition. Similarly, I hypothesize that excitation of the mTH during a task requiring cognitive
flexibility will rescue ASI-induced cognitive deficits. Based on the necessity of adolescent mTH activity for proper
PFC maturation, and the role of thalamo-prefrontal circuitry in adult cognitive flexibility, I hypothesize that
adolescent thalamic excitation during social isolation will prevent formation of long-term cognitive deficits. I will
excite all PFC-projecting neurons in a similar manner. To test these hypotheses, I will be trained in and employ
a combination of, optogenetics, chemogenetics transgenic mouse lines, and targeted viral strategies.
Additionally, I will be trained on machine learning tools for histology registration and segmentation, decoding and
clustering of cell distribution patterns, and unbiased behavioral scoring.
The identification of an early critical period of socially guided brain development may provide a window
for intervention to prevent or slow development of cognitive symptoms in adolescence. If proven, my hypotheses
point to adolescents as an ideal target for interventions aimed to increase social connectedness in individuals at
high risk of developing schizophrenia and other psychiatric disorders. Studying both male and female brains will
ensure that individuals of both sexes can benefit from scientifically informed intervention and treatment.

Grant Number: 5F31MH136812-02
NIH Institute/Center: NIH
Principal Investigator: Isabel Bravo