Seminars

Abuse, neglect, and other forms of uncontrollable stress during childhood and early adolescence can lead to adverse outcomes later in life, including especially perturbations in the regulation of mood and emotional states, and specifically anxiety disorders and depression. However, stress experiences vary from one individual to the next, meaning that causal relationships and mechanistic accounts are often difficult to establish in humans. This interdisciplinary talk considers the value of research in experimental animals where stressor experiences can be tightly controlled and detailed investigations of molecular, cellular, and circuit-level mechanisms can be carried out. The talk will focus on the widely used repeated maternal separation procedure in rats where rat offspring are repeatedly separated from maternal care during early postnatal life. This early life stress has remarkably persistent effects on behaviour with a general recognition that maternally-deprived animals are susceptible to depressive-like phenotypes. The validity of this conclusion will be critically appraised with convergent insights from a recent longitudinal study in maternally separated rats involving translational brain imaging, transcriptomics, and behavioural assessment.

Executive control processes and flexible behaviors rely on the integrity of, and dynamic interactions between, large-scale functional brain networks. The right insular cortex is a critical component of a salience/midcingulo-insular network that is thought to mediate interactions between brain networks involved in externally oriented (central executive/lateral frontoparietal network) and internally oriented (default mode/medial frontoparietal network) processes. How these brain systems reconfigure with development is a critical question for cognitive neuroscience, with implications for neurodevelopmental pathologies affecting brain connectivity. I will describe studies examining how brain network dynamics support flexible behaviors in typical and atypical development, presenting evidence suggesting a unique role for the dorsal anterior insular from studies of meta-analytic connectivity modeling, dynamic functional connectivity, and structural connectivity. These findings from adults, typically developing children, and children with autism suggest that structural and functional maturation of insular pathways is a critical component of the process by which human brain networks mature to support complex, flexible cognitive processes throughout the lifespan.

To build an appropriate representation of the sensory stimuli around the world, neural circuits are wired according to both intrinsic factors and external sensory stimuli. Moreover, the brain circuits have the capacity to rewire in response to altered environment, both during early development and throughout life. In this talk, I will give an overview about my past research in studying the dynamic processes underlying functional maturation and plasticity in rodent sensory cortices. I will also present data about the current and future research in my lab – that is, the synaptic and circuit mechanisms by which the mature brain circuits employ to regulate the balance between stability and plasticity. By applying chronic 2-photon calcium and close-loop visual exposure, we studied the circuit changes at single-neuron resolution to show that concurrent running with visual stimulus is required to drive neuroplasticity in the adult brain.

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we have adopted a symptom-to-circuit approach in theFmr1-/- mouse model of Fragile X syndrome (FXS). Using a go/no-go task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons in primary visual cortex, and a decrease in the activity of parvalbumin (PV) interneurons. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioural performance. Strikingly, human subjects with FXS exhibit similar impairments in visual discrimination as Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in FXS. More recently, we find that the ability of Fmr1-/- mice to perform the visual discrimination task is also drastically impaired in the presence of visual or auditory distractors, suggesting that sensory hypersensitivity may affect perceptual learning in autism.