-  Neuroprotection of the developing brain:  a role for oxytocin? -

University of Geneva, Faculty of Medecine, Dépt of paediatrics -  Switzerland

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two complications of human pregnancy are the leading causes of ante/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders in more than 9 million children each year. The lack of validated strategies to prevent handicaps linked to prematurity and IUGR underscore the need for further research to identify determinants involved in the vulnerability of the developing brain. Perinatal inflammation, a key factor associated with prematurity and IUGR, is recognized to activate microglia, the resident macrophages of the central nervous system, and to sensitize the developing brain to a secondary hypoxic or excitatory insult. Microglial cells can acquire distinct phenotypes in response to perinatal stimuli that allow them to either disrupt developmental processes, ie. myelination, synaptic pruning or axonal growth, or support repair and regeneration. These diverse roles make microglia critical modulators of brain development and injury and the key issue addressed in this proposal is how microglia could be regulated to alleviate the consequences of perinatal inflammation on brain development.

The talk by Olivier Baud derives from his previous and recent studies on Oxytocin (OXT), an essential hormone during the perinatal period and parturition that is implicated in the regulation of central inflammatory response to injury in the mature brain. In the developing brain, he recently reported an association between IUGR, low expression of OXT and neuroinflammation, leading to defective myelination and abnormal brain function.
Pharmacological treatment using carbetocin, a brain permeable long-lasting OXT receptor (OXTR) agonist, was found to be associated with a significant reduction of microglial activation and provided long-term neuroprotection.

The protective role of OXT in the developing brain through the modulation of microglial activation will be further studied by using novel research strategies in a translational perspective. These perspectives are expected to have several impacts not only restricted to the newborn, including basic insights into microglial cell physiology and reactivity and its consequences on structural and functional development of the brain. It will ultimately
guide future pharmaceutical development and clinical trials to test OXT as a relevant candidate to control neuroinflammation.

Hippocampal pyramidal cells fire selectively to build abstract representations of a contingency of visual, auditory, somatosensory and behavioural events. While moving around these “spaces”, sequences of hippocampal “place cells” are activated in an orderly manner coordinated by the theta rhythm (4-12 Hz). One mechanism determining these sequences is theta phase precession, which occurs anytime the animal traverses a “place field”. However, hippocampal cells also exhibit a specific phase preference, which can be influenced by the global brain state.

Here, we aim to study factors underlying theta phase preference across deep and superficial CA1 pyramidal sublayers during theta oscillations. First, we obtained juxtacellular and multi-site recordings in awake head-fixed mice and freely-moving rats. We found a characteristic bimodality in the distribution of the preferred firing phases of CA1 pyramidal cells. In order to understand the underlying factors, we built a biophysically realistic model that includes most of the known excitatory and inhibitory inputs converging in deep and superficial cells. The sublayer location was one factor explaining firing bimodality, but we found other influencing axes as well such as entorhinal and intra-hippocampal inputs.

We tested some of the model predictions using cell-type specific chemogenetic approaches and unsupervised dynamical analysis of LFP activity. We discuss on the multiple dimensions determining phase preference and speculate about their potential role in defining episodic memory function.

Invited by : Françoise MUSCATELLI

Inmed meeting room, Monday February 10th, 11 am

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