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Project title
Maturation of gamma oscillation, microglial function, and inhibitory circuitry in the dorsal horn of the spinal cord during the postnatal development
Supervisors names
Simon Beggs
Madeleine Verriotis
Background
Gamma oscillation is a neural activation pattern well known for its role in sensory processing and cognitive functions (Fries, 2015). Parvalbumin-expressing (PV) interneurons are critically involved in generating cortical oscillations in the gamma range; the rhythmic inhibition resultant from synchronous activity of fast-spiking inhibitory PV interneurons is thought to produce neural ensemble synchrony by generating a narrow window for effective excitation. Although very little is known about the role of nonneuronal cells in gamma rhythms, recent evidence indicates that evoked gamma produces glial responses.
Gamma, microglia and PV interneurons mature during the first few weeks of life in mice, and their interaction during the early postnatal life is likely to regulate the refinement of neural circuits (Goldberg et al., 2011). During this period, PV-mediated inhibition is required for normal refinement of synaptic connectivity and critical period plasticity (Katagiri et al., 2007). Loss or dysregulation of interneurons during development gives rise to impaired gamma oscillations and spike timing in cortical circuits, widely observed in neurodevelopmental and psychiatric disorders, including autism and schizophrenia.
The normal postnatal refinement of sensory circuits in the dorsal horn of the spinal cord is essential to integrate and process somatosensory information. Given their developmental role in the neocortex, we hypothesize that maturation of the dorsal horn PV interneuron-mediated inhibition is required for the postnatal refinement of somatosensory circuits and development of gamma oscillations. Importantly, the crosstalk between neurons and glial cells is essential for neuronal circuit maturation during development. Microglia modulate neuronal activity and neural activity, in turn, is thought to refine the neural circuitry through the synaptic pruning by postnatal microglia to remove redundant synapses.
Aims
Based on these findings, the project aims to investigate the developmental progression of PV interneuron-related gamma oscillations and microglial maturation in the spinal dorsal horn during the early postnatal period.
Methods
The time course of gamma activity maturation will be recorded by measuring peripheral sensory-evoked local field potentials (LFPs) in the dorsal horn across postnatal ages and mapped onto that of inhibitory circuitry and microglia maturation, recorded by measuring the postnatal changes in the intrinsic properties of PV interneurons and microglial cell density and phagocytic activity, respectively. The developmental role of gamma oscillation in the spinal cord will be studied by driving gamma activity during the first postnatal week when the oscillations have not yet emerged and examining its effect on microglial activity, dorsal horn circuits and somatosensory behaviours.
Despite the critical involvement of microglial pruning activity in postnatal maturation of dorsal horn and sensory processing in adulthood, the underlying mechanisms remain elusive. The long-term functional and behavioural alterations of sensory processing will be assessed through pharmacological and/or genetic disruption of microglial pruning activity during early postnatal life.
Timeline
The project requires the use of several sophisticated techniques; in vivo electrophysiology, behaviour and advanced histology and imaging. Full training will be provided. The scope of the project is achievable within the three year time frame.
References
Bitzenhofer et al 2020 eLife 9 e56795
Fries 2015 Neuron 88; 220-235
Goldberg et al 2011 Cereb Cortex 21; 666-682
Katagiri et al 2007 Neuron; 805-812
Stedehouder et al 2018 J Neurosci 38; 3631-3642
Contact
Simon Beggs s.beggs@ucl.ac.uk