Sarah E. Canetta, PhD

My laboratory investigates the neural circuitry of cognitive and affective behaviors, with a particular focus on how experiences encountered during ‘sensitive periods’ shape the development of this circuitry and impact behavior all the way into adulthood.  To do this, we use a multi-disciplinary investigative strategy in mice including in vivo recordings of activity during behavior, opto- and pharmacogenetic manipulations of circuit activity and measurements of synaptic function and anatomy using in vitro slice electrophysiology and histology.  Through this approach we hope to gain insight into the typical developmental trajectory of brain circuits supporting cognitive and affective behaviors, as well as the etiology of cognitive and affective symptoms associated with disorders like schizophrenia, anxiety, depression and substance abuse. 

The concept of sensitive periods is essential to our understanding of how the environment shapes brain development.  However, the study of sensitive periods in cortical development has predominantly focused on sensory regions, where sensory experiences refine cortical development via alterations in activity.  We have recently identified a prefrontal adolescent sensitive period in which transiently decreasing the activity of a population of interneurons that express the molecular marker, parvalbumin (PV), leads to long-lasting effects on the integration of these cells in prefrontal circuitry, prefrontal network function and behavioral flexibility measured in an extradimensional set-shifting task (Canetta et al, bioRxiv, 2021).  This finding demonstrates the necessity of neuronal activity for prefrontal cortical circuit development and addresses the long-standing question in the field regarding whether there are activity-dependent sensitive time windows governing the maturation of this structure, similar to what has been seen in the sensory cortex.  This finding also serves as the basis for several ongoing interests of the lab: 1) What are the mechanisms that determine the timing of this sensitive period for heightened plasticity for activity-dependent remodeling? and 2) What are environmental experiences or factors that modulate endogenous PV interneuron activity during development?

While studying cognitive flexibility in the adult animal, we identified a new mechanism by which the prefrontal cortex regulates extradimensional set-shifting behavior. Specifically, we identified a task-induced increase in gamma frequency power when mice are preparing to make a choice during set-shifting. This induction in gamma oscillatory power was only observed in correct, but not incorrect, trials, and predicted whether mice subsequently made correct or incorrect choices.  Another project in the laboratory is focused on understanding how PV interneurons utilize gamma oscillations to organize the activity of task-relevant neuronal ensembles to support set shifting behavior.

A final project in the laboratory is examining how brief, early postnatal exposure to the selective serotonin reuptake inhibitor, fluoxetine (FLX), results in increases in affective behavior in adulthood that are resistant to subsequent chronic treatment with FLX, but normalized by treatment with the atypical antidepressant, tianeptine (Pekaraskaya & Holt et al, bioRxiv, 2020).   Mouse brain development occurring during this postnatal exposure window is comparable to brain development occurring in the third trimester of a human pregnancy, making these developmentally FLX-exposed mice a model of human exposure to SSRIs in utero.  Focusing on reward processing, we are investigating the neural circuit underpinnings of this SSRI-resistance as well as how tianeptine remains effective in this early exposure model.  The goal of these studies is to define the neurophysiological and behavioral mechanisms underlying different antidepressant pharmacotherapies, as well as improve our understanding of why they can be ineffective in certain individuals.