01. Molecular and physiological mechanisms of plasticity in inhibitory circuits
How does learning and experience affect the anatomy and physiology of different types of inhibitory neurons?
Inhibitory interneurons that use GABA as neurotransmitter play a critical role in cortial information processing. Shown above is an image of GABAergic inhibitory neurons (green) and a subpopulation of them, the parvalbumin neuron (red) in a slice culture of the hippocampus. Blue marks all nuclei (DAPI). We previously showed that homozygous deletion of Gad1 gene, which codes for GAD67 protein, reduced the amplitudes of miniature IPSCs, suggesting a presynaptic locus of modulation of GABAergic transmission strength. We also recently showed that specific deletion of TrkB, a major BDNF receptor, in parvalbumin (PV) interneurons reduces their neural excitability and inhibitory output. Unexpectedly, reduction of PV neuronal output ultimately leads to lower but not higher excitation-inhibition ratio in the cortex. We are currently looking into how sensory experience modifies inhibitory circuits in the cortex.
How do neurological disorders such as epilepsy and Alzheimer's Disease trigger maladaptive plasticity of GABAergic circuits and exhibition-inhibition imbalance in the brain?
Recent advances in genetics has revealed a large number of genes that contribute to various neurological disorders. What are the molecular and physiological signatures of the dysfunction? We use whole-cell patch-clamp electrophysiology to investigate the molecular and synaptic changes in single neurons (image above, filled during electrophysiological recording) in disease. GAD67 and PV protein expression can be used as proxy for GABAergic synaptic strength. We are currently studying how inhibitory circuits are dysregulated in epilepsy.
03. Functional organization of olfactory cortex
How are circuits in the cortex functionally organized to stably represent stimulus AND plastically adapt representation in response to learning?
The piriform cortex is the largest cortical region receiving inputs from the olfactory bulb and can perform context-dependent representation of odor information. We know that the piriform cortex contains a mix of feedforward and recurrent connections, but how does this help with coding of odors as well as learning associations? The above left is a circuit diagram of what we believe is a hierarchical organization of feedback projections from the piriform to the OB. Superficial pyramidal (SP), but not semilunar (SL), cells send projections back to the OB, suggesting neuron-type specific rules for cortical connectivity. Above right is a confocal image of SL neurons (green, 48L mouse) injected with a red retrograde dye injected into the OB. There is no overlap of the green SL population and red SP population in layer 2 of the piriform cortex, revealing their connectivity pattern. We are currently examining how inhibitory circuits differentially modulate these specific output circuits of the piriform.