Christian Mirescu

Early life experience alters response of adult neurogenesis to stress

Maternal deprivation produces persistent abnormalities in behavioral and neuroendocrine functions associated with the hippocampus, a brain region that shows considerable structural change in response to experience throughout life. Here we show that adverse experience early in life affects the regulation of adult neurogenesis in the hippocampus. More specifically, a decrease in cell proliferation and immature neuron production are observed in the dentate gyrus of adult rats that are maternally separated as pups. Although maternally separated rats show normal basal levels of corticosterone, the suppression of cell proliferation in these rats can be reversed by lowering corticosterone below the control value. In addition, normal stress-induced suppression of cell proliferation and neurogenesis, despite normal activation of the hypothalamic pituitary adrenal (HPA) axis, is not observed in maternally separated rats. Our results suggest that early adverse experience inhibits structural plasticity via hypersensitivity to glucocorticoids and diminishes the ability of the hippocampus to respond to stress in adulthood.

Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids

Prolonged sleep deprivation is stressful and has been associated with adverse consequences for health and cognitive performance. Here, we show that sleep deprivation inhibits adult neurogenesis at a time when circulating levels of corticosterone are elevated. Moreover, clamping levels of this hormone prevents the sleep deprivation-induced reduction of cell proliferation. The recovery of normal levels of adult neurogenesis after chronic sleep deprivation occurs over a 2-wk period and involves a temporary increase in new neuron formation. This compensatory increase is dissociated from glucocorticoid levels as well as from the restoration of normal sleep patterns. Collectively, these findings suggest that, although sleep deprivation inhibits adult neurogenesis by acting as a stressor, its compensatory aftereffects involve glucocorticoid-independent factors.

Effects of Standardized Extracts of St. John's Wort on the Single-Unit Activity of Serotonergic Dorsal Raphe Neurons in Awake Cats: Comparisons with Fluoxetine and Sertraline

St. Johns wort is widely used as an herbal remedy for depression. Although its mechanism of action remains unknown, some evidence suggests that St. Johns wort might act via brain serotonin (e.g., as a serotonin reuptake inhibitor). To determine whether St. Johns wort affects the central serotonergic system, we monitored the discharge rate of serotonin-containing neurons in the dorsal raphe nucleus of awake cats following systemic administration of two clinical preparations of St. Johns wort, Jarsin® 300 (15–600 mg/kg, p.o.) and Hyperforat® (0.5–4.0 ml, i.v.). Both preparations were found to have no effect on neuronal activity. This contrasts sharply with the action of fluoxetine and sertraline (2 mg/kg, p.o.), two selective serotonin reuptake inhibitors (SSRIs), which markedly depressed neuronal activity by increasing the synaptic availability of serotonin at inhibitory somatodendritic 5-HT1A autoreceptors. The failure of St. Johns wort to depress neuronal activity cannot be attributed to an impairment of the 5-HT1A autoreceptor mechanism, since pretreatment with Jarsin® 300 (300 mg/kg, p.o.) did not alter the responsiveness of serotonergic neurons to the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10 μg/kg, i.v.). Overall, these findings indicate that the mode of action of St. Johns wort is different from that of conventional antidepressant drugs, which elevate brain serotonin and evoke negative feedback control of serotonergic neurons.

Stem Cells in the Adult Brain

The adult mammalian brain has vastly reduced regenerative potential compared with the developing brain. Nevertheless, cell proliferation occurs in the adult brain, as does neurogenesis, and cells that generate neurons and glia in vivo and in vitro have been identified in the adult central nervous system (CNS). As our understanding of the factors that regulate stem cell proliferation and neurogenesis in the adult brain deepens, the development of methods directed at repairing the damaged brain through the transplantation of cultured cells or through the induction of endogenous neurogenesis in selected neuronal populations may lead to novel therapeutic strategies. This chapter reviews the evidence that neural stem cells exist in the adult brain and describes the factors that determine whether these cells divide and, if so, the fate of their progeny.

From neurotoxin to neurotrophin

Glucocorticoids are important for neuronal function, but their release in conjunction with a brain injury can intensify neuronal death, causing more harm than good. A new study shows that delivery of genes that have been modified to alter glucocorticoid signaling can block the toxic effects of the hormone in vitro and in vivo, converting what was once a neurons worst enemy into its best friend.

A Critical Time for New Neurons in the Adult Hippocampus

Despite the vast literature on adult neurogenesis in the mammalian hippocampus, the function of these new neurons remains unclear. New neurons are generated in the dentate gyrus with estimates ranging on the order of thousands added per day in rodents. These newly born cells can differentiate into

Neuronal Progenitors in the Adult Brain: From Development to Regulation

Publisher Summary Cell proliferation occurs in the adult brain, as does neurogenesis, and cells that give rise to neurons and glia in vivo and in vitro have been identified in the adult central nervous system (CNS). Studies have identified cells with stem cell–like properties in the adult mammalian brain. The bulk of evidence suggests that these cells exhibit characteristics of glial cells, a finding that may elucidate basic mechanisms of neurogenesis and make isolating stem cells a more tractable problem. This chapter reviews the evidence that neural stem cells exist in the adult brain. It also discusses the factors that determine whether these cells divide and, if so, what is the fate of their progeny. The production of new neurons in the adult brain has been shown to be regulated by growth factors, neurotransmitters, and hormones. A more detailed understanding of the potential interactions among these modulators of adult neurogenesis may enable the controlled manipulation of neuron production in the damaged brain. Numerous neurological conditions are associated with the loss of neural cells. The key advantage of transplanting cell lines is that they can be genetically engineered, allowing for customization depending upon the specific disease. As an understanding of the factors that regulate stem cell proliferation and neurogenesis in the adult brain deepens, the development of methods directed at repairing the damaged brain through transplantation of cultured cells, or through induction of endogenous neurogenesis in selected neuronal populations, may lead to novel therapeutic strategies.

Neuronal Progenitors in the Adult Brain

Publisher Summary Cell proliferation occurs in the adult brain, as does neurogenesis, and cells that give rise to neurons and glia in vivo and in vitro have been identified in the adult central nervous system (CNS). Studies have identified cells with stem cell–like properties in the adult mammalian brain. The bulk of evidence suggests that these cells exhibit characteristics of glial cells, a finding that may elucidate basic mechanisms of neurogenesis and make isolating stem cells a more tractable problem. This chapter reviews the evidence that neural stem cells exist in the adult brain. It also discusses the factors that determine whether these cells divide and, if so, what is the fate of their progeny. The production of new neurons in the adult brain has been shown to be regulated by growth factors, neurotransmitters, and hormones. A more detailed understanding of the potential interactions among these modulators of adult neurogenesis may enable the controlled manipulation of neuron production in the damaged brain. Numerous neurological conditions are associated with the loss of neural cells. The key advantage of transplanting cell lines is that they can be genetically engineered, allowing for customization depending upon the specific disease. As an understanding of the factors that regulate stem cell proliferation and neurogenesis in the adult brain deepens, the development of methods directed at repairing the damaged brain through transplantation of cultured cells, or through induction of endogenous neurogenesis in selected neuronal populations, may lead to novel therapeutic strategies.

Chapter 20 – Neuronal Progenitors in the Adult Brain: From Development to Regulation

Publisher Summary Cell proliferation occurs in the adult brain, as does neurogenesis, and cells that give rise to neurons and glia in vivo and in vitro have been identified in the adult central nervous system (CNS). Studies have identified cells with stem cell–like properties in the adult mammalian brain. The bulk of evidence suggests that these cells exhibit characteristics of glial cells, a finding that may elucidate basic mechanisms of neurogenesis and make isolating stem cells a more tractable problem. This chapter reviews the evidence that neural stem cells exist in the adult brain. It also discusses the factors that determine whether these cells divide and, if so, what is the fate of their progeny. The production of new neurons in the adult brain has been shown to be regulated by growth factors, neurotransmitters, and hormones. A more detailed understanding of the potential interactions among these modulators of adult neurogenesis may enable the controlled manipulation of neuron production in the damaged brain. Numerous neurological conditions are associated with the loss of neural cells. The key advantage of transplanting cell lines is that they can be genetically engineered, allowing for customization depending upon the specific disease. As an understanding of the factors that regulate stem cell proliferation and neurogenesis in the adult brain deepens, the development of methods directed at repairing the damaged brain through transplantation of cultured cells, or through induction of endogenous neurogenesis in selected neuronal populations, may lead to novel therapeutic strategies.

20 – Stem Cells in the Adult Brain

This chapter reviews the evidence that neural stem cells exist in adult brain and describes the factors that determine whether these cells divide and, in that case, the fate of their progeny. The adult mammalian brain has vastly reduced regenerative potential compared to the developing brain. Nevertheless, cell proliferation occurs in the adult brain, as does neurogenesis, and cells that generate neurons and glia in vivo and in vitro have been identified in the adult central nervous system (CNS). Although studies dating to the 1960s have documented neurogenesis in the adult mammalian brain, the isolation of cells with stem cell properties, that is, multipotent and self-renewing, from adult neural tissue did not occur until much later. Since that time, numerous reports have identified cells from adult animals with the potential to produce neurons and glia when grown in culture or transplanted into other brain regions. These cells have been isolated from a variety of locations in the CNS, including the spinal cord, the hippocampus, the neocortex, and the striatum. Adult-generated neurons appear to use radial glia processes as migratory guides to their final destination in the rostral forebrain.