The hypothalamus controls diverse homeostatic functions including fertility. Neural episode generators are required to drive the intermittent pulsatile and surge profiles of reproductive hormone secretion that control gonadal function. Studies in genetic mouse models have been fundamental in defining the neural circuits forming these central pattern generators and the full range of in vitro and in vivo optogenetic and chemogenetic methodologies have enabled investigation into their mechanism of action. The seminar will outline studies defining the hypothalamic “GnRH pulse generator network” and current understanding of its operation to drive pulsatile hormone secretion.

Migraine is much more than an episodic headache. It is a complex brain disorder, characterized by a global dysfunction in multisensory information processing and integration. In a third of patients, the headache is preceded by transient sensory disturbances (aura), whose neurophysiological correlate is cortical spreading depression (CSD). The molecular, cellular and circuit mechanisms of the primary brain dysfunctions that underlie migraine onset, susceptibility to CSD and altered sensory processing remain largely unknown and are major open issues in the neurobiology of migraine. Genetic mouse models of a rare monogenic form of migraine with aura provide a unique experimental system to tackle these key unanswered questions. I will describe the functional alterations we have uncovered in the cerebral cortex of genetic mouse models and discuss the insights into the cellular and circuit mechanisms of migraine obtained from these findings.

Brain and neuronal network development depend on a complex sequence of events, which include neurogenesis, migration, differentiation, synaptogenesis, and synaptic pruning. Perturbations to any of these processes, for example associated with ion channel gene mutations (i.e., channelopathies), can underlie neurodevelopmental disorders such as neonatal and infantile epilepsies, strongly impair psychomotor development and cause persistent deficits in cognition, motor skills, or motor control. The therapeutic options available are very limited, and prophylactic therapies for patients at an increased risk of developing such epilepsies do not exist yet. By using genetic mouse models in which we controlled the activities of Kv7/M or HCN/h-channels during different developmental periods, we obtained offspring with distinct neurological phenotypes that could not simply be reversed by the re-introduction of the affected ion channel in juvenile or adult animals. The results indicate that channelopathy/mutation-specific treatments of neonatal and infantile epilepsies and their comorbidities need to be targeted to specific sensitive periods.