Activity-dependent maturation of brain circuits

Activity-dependent maturation of olfactory bulb circuits in development and adulthood

The olfactory bulb (OB) is the first region of the brain to process smell information arriving from the nose, and is also a fantastic model system for studying activity-dependent neuronal maturation. Not only are OB circuits set up in an activity-dependent manner during early postnatal development, they are also continually altered throughout life as a consequence of cellular plasticity and ongoing adult neurogenesis. Our work focuses particularly on the bulb’s glomerular layer, where incoming sensory inputs are extensively modulated by local circuitry before being relayed to cortex. Within this glomerular network is a sizeable population of dopaminergic (DA) interneurons that co-release both GABA and dopamine to regulate transmission of olfactory information to bulbar projection neurons. These DA neurons are known to be extremely plastic, regulating expression of their transmitter synthesising enzymes. They are even plastic to the point of whole-neuron replacement, forming part of the OB interneuron population continually turned over throughout life via adult neurogenesis. But how do cellular mechanisms of plasticity interact with postnatal neurogenesis to enable DA neurons to control sensory processing at the first stages of olfaction? Our initial work on this key question demonstrated a novel form of structural plasticity in OB DA neurons in dissociated culture. We are now focusing our attention on plastic changes induced in these cells by manipulations of sensory activity in vivo. By drawing on our existing expertise in manipulating neuronal activity and our experience in monitoring neuronal function ex vivo and in vivo, we aim to understand how cellular mechanisms of plasticity in individual types of neuron are integrated to modulate information processing in neuronal networks, and how this ultimately controls whole-organism behaviour.

Activity-dependent plasticity at the axon initial segment (AIS)

In neurons, the axon initial segment is a highly specialised structure near the start of the axon that is crucial for controlling action potential initiation and axonal identity. We have uncovered evidence for a surprising amount of plasticity at the AIS: in vitro, the structure can change its length or its axonal location dependent on cells’ recent history of patterned electrical activity. These changes are associated with alterations in neuronal excitability, and may represent an adaptational response to perturbed activity levels. We have shown that this novel form of structural plasticity can be bidirectional and cell-type-specific, and that it depends on signalling through CaV1 channels and (in dentate granule cells of the hippocampus, at least) on the calcium-dependent phosphatase calcineurin. We’re now continuing to study AIS plasticity in vivo, with a focus – of course! – on olfactory bulb neurons and the impact that AIS changes, along with other integrated forms of cellular plasticity, can have on information processing in sensory circuits.