Ana Catarina Oliveira Ferreira - ICVS, University of Minho
Title: Lipocalin-2 regulates adult neurogenesis and contextual discriminative behaviors
Abstract:
In the adult mammalian brain, newborn granule cells are continuously generated from resident adult neural stem cells (NSCs), and integrated into hippocampal circuits, thus contributing for hippocampal function. In fact, hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Thus, the identification of factors that control NSCs maintenance, differentiation and integration is essential.
In recent years, the iron trafficking protein lipocalin-2 (LCN2) has emerged as a novel regulator of brain processes and behaviour, involved in neural structure and remodelling, anxiety-like behaviours and cognitive function. Here, we show that the deletion of LCN2 induces deficits in NSCs proliferation and commitment, with impact on the hippocampal-dependent contextual fear discriminative task. Mice deficient in LCN2 present a significant increase in the NSCs population, as a consequence of a G0/G1 cell cycle arrest induced by increased endogenous oxidative stress. Of notice, treatment with the iron chelating agent deferoxamine rescues NSCs oxidative stress, promotes cell cycle progression and neurogenesis, and improves contextual fear conditioning. This indicates that LCN2 is a novel key modulator of neurogenesis that, through iron cell content modulation, controls NSCs cell cycle progression and death, self-renewal, proliferation and differentiation and, ultimately, hippocampal function. Altogether, our findings identify novel mechanisms of hippocampal neurogenesis regulation in the adult brain, and opens perspectives in understanding the role of iron and iron-related regulators in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function.
Title: Lipocalin-2 regulates adult neurogenesis and contextual discriminative behaviors
Abstract:
In the adult mammalian brain, newborn granule cells are continuously generated from resident adult neural stem cells (NSCs), and integrated into hippocampal circuits, thus contributing for hippocampal function. In fact, hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Thus, the identification of factors that control NSCs maintenance, differentiation and integration is essential.
In recent years, the iron trafficking protein lipocalin-2 (LCN2) has emerged as a novel regulator of brain processes and behaviour, involved in neural structure and remodelling, anxiety-like behaviours and cognitive function. Here, we show that the deletion of LCN2 induces deficits in NSCs proliferation and commitment, with impact on the hippocampal-dependent contextual fear discriminative task. Mice deficient in LCN2 present a significant increase in the NSCs population, as a consequence of a G0/G1 cell cycle arrest induced by increased endogenous oxidative stress. Of notice, treatment with the iron chelating agent deferoxamine rescues NSCs oxidative stress, promotes cell cycle progression and neurogenesis, and improves contextual fear conditioning. This indicates that LCN2 is a novel key modulator of neurogenesis that, through iron cell content modulation, controls NSCs cell cycle progression and death, self-renewal, proliferation and differentiation and, ultimately, hippocampal function. Altogether, our findings identify novel mechanisms of hippocampal neurogenesis regulation in the adult brain, and opens perspectives in understanding the role of iron and iron-related regulators in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function.