The Activity of Developing Sensory Networks
Our lab seeks to understand the secret life of the fetal and infant brain. In particular, we are studying the development of activity in the cerebral cortex and its connected subcortical structures.
Our goal is to identify the early circuit changes that cause the maturation of brain activity. Using an animal model and EEG data from human infants born pre-term, we study how network changes are related to changes in infant behavior, and how they support brain and cognitive maturation.
Far from being a passive recipient of information from the outside world, our work is beginning to reveal active mechanisms used by the fetal brain to shape activity into a form uniquely suited for its own development. Our work on a validated animal model of fetal development has documented several unique specializations of the fetal and infant brain. These include:
1) "Booster" circuits that amplify weakly connected inputs such as those from the infant's retina to the thalamus.
2) An all-or-none "Bursting" mode of information processing by fetal cortex, that switches to the mature, higher resolution "Acuity" mode just before birth. This means the fetal brain is unlikely to process complex stimuli (like Mozart), in a normal way.
3) A complete absence of the ability to generate a state of wakefulness in cortex until just before the onset of high-quality sensory experience at eye opening (or birth in humans).
Atypical Activity in Developmental Disorders
Having a normal timeline of fetal cortical activity development in rats, mice, and humans is an important first step to identifying disrupted circuits in animal models of disease.
We are using this normal timeline to identify deviations in the development of cortical activity in animal models of neurodevelopmental disorders.
Using this approach, we have identified several new phenotypes in the rat model of Fragile X syndrome, at ages earlier than symptoms are usually observed. For example, we have found a paradoxical arousal in the cortex of infant Fragile X rats when the animal is behaviorally at rest. This suggests that unlike their wild-type littermates, infant Fragile X rats are unable to suppress cortical arousal to unattended stimuli.
This approach has also allowed us to identify which activity appears to develop normally. For example, the developmental trajectory of spontaneous activity is relatively normal in infant Fragile X rat cortex, but visual evoked activity is hypo-excitable.
Tools & Techniques
Prenatal brain activity is a challenging topic of investigation that relies on analysis of electroencephalograms (EEGs) from infants born preterm. EEGs represent the summed activity from surface electrodes, and can give only a general picture of the complex networks active in the structures below each probe. To understand and deconstruct the meaning of EEGs, we have developed an animal model that closely mirrors all of the major stages of fetal cortical activity development. In collaboration with neonatologists, we developed a timeline of activity development using EEG in human preterm infants at multiple stages of gestation. By using identical paradigms to measure and analyse EEG activity in human and animal models, we created a reference timeline that aligned cortical activity development in both species.
Using this animal model in the laboratory, we make high resolution measurements of electrical activity throughout the depth of cortex using advanced multi-electrode arrays in awake neonatal and developing rodents. With careful targeting, we are able to simultaneously record from inputs to cortex in the thalamus and other sub-cortical structures. Using whole-cell electrophysiology, we can then measure the intracellular activity of a single neuron in an awake animal, while recording the ensemble activity of the network. The high temporal precision of these techniques are especially well suited to understanding network changes in development, including active states. We are also using calcium imaging in vivo to understand the spatial relationship of these changes.
We use optogenetics, pharmacological manipulation, genetically modified rodents, and viral mediated gene delivery to stimulate or inactivate specific cell types, inputs, synapses, or brain regions to understand their role in developing neural circuits. These are combined with measurements of both intrinsic, spontaneous activity, and sensory evoked activity in developing rodents as they cycle through stages of sleep, quiet waking, and behavioral arousal.
Signal processing is an essential part of our work. Algorithms already established for analysis of adult neural signals are not always useful in the developing brain, when activity is dramatically different. We are continually working to create unbiased analysis tools for the developing brain, including novel spectral analysis and spike sorting tools.
The Neonatal Rodent as a Model of Fetal Human Brain Development
The Developmental Origin of Brain States Supporting Consciousness
Neural Circuit Function in the Diseased Juvenile Brain
Infantile Cortical Activity as a Marker for Autism?