ABSTRACT
Rakic and colleagues challenge the use of extensively validated adult hippocampal neurogenesis (AHN) markers and postulate an alternative interpretation of some of the data included in our study. In Terreros-Roncal et al., reconstruction of the main stages encompassed by human AHN revealed enhanced vulnerability of this phenomenon to neurodegenerative diseases. Here, we clarify points and ambiguities raised by these authors.
Subject(s)
Hippocampus , Neurodegenerative Diseases , Neurogenesis , Adult , Biomarkers/metabolism , Hippocampus/embryology , Hippocampus/metabolism , Humans , Neurodegenerative Diseases/metabolismABSTRACT
Alvarez-Buylla and colleagues provide an alternative interpretation of some of the data included in our manuscript and question whether well-validated markers of adult hippocampal neurogenesis (AHN) are related to this phenomenon in our study. In Terreros-Roncal et al., reconstruction of the main stages of human AHN revealed its enhanced vulnerability to neurodegeneration. Here, we clarify ambiguities raised by these authors.
Subject(s)
Neurodegenerative Diseases , Adult , Hippocampus/physiology , Humans , Neurogenesis/physiologyABSTRACT
Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.
Subject(s)
Hippocampus/physiopathology , Neurodegenerative Diseases/physiopathology , Neurogenesis , Adult , Aged , Aged, 80 and over , Aging , Amyotrophic Lateral Sclerosis/physiopathology , Cell Proliferation , Dentate Gyrus/blood supply , Dentate Gyrus/pathology , Dentate Gyrus/physiopathology , Female , Frontotemporal Dementia/physiopathology , Hippocampus/pathology , Humans , Huntington Disease/physiopathology , Lewy Body Disease/physiopathology , Male , Microglia/physiology , Middle Aged , Neural Stem Cells/physiology , Neurodegenerative Diseases/pathology , Parkinson Disease/physiopathology , PhagocytosisABSTRACT
The exposure of rats to an enriched environment (EE) has several effects in common with the administration of antidepressants. However, there is still little information about the molecular underpinnings of these effects on rats subjected to experimental models of depression. The aim of this research was to evaluate the effects of EE on rats exposed to the learned helplessness paradigm (LH), a well-known model of the disease. We found that a 21 day exposure to EE reverts helplessness behavior to normal in LH animals. Inmunohistochemical labeling showed that this effect was accompanied by normalization of two structural proteins of hippocampal neurons to control values: the light neurofilament subunit (NFL) and the postsynaptic density 95 (PSD-95) protein, which were decreased in LH animals housed in standard cages. The decrease in the presynaptic protein synaptophysin (SYN) observed in LH animals remained unchanged after exposure to EE. There was no increase in neurogenesis as measured by quantification of double-labeled cells with 5-bromo-2'-deoxyuridine (BrdU) and the neuronal marker beta-tubulin class III. These results show that EE may have behavioral and synaptic effects on animals exposed to an experimental model of depression, and that such actions seem to be independent from neurogenesis.
Subject(s)
Cytoskeleton/metabolism , Depressive Disorder/metabolism , Depressive Disorder/therapy , Environment, Controlled , Hippocampus/metabolism , Synapses/metabolism , Animals , Bromodeoxyuridine , Cytoskeleton/ultrastructure , Depressive Disorder/physiopathology , Disease Models, Animal , Disks Large Homolog 4 Protein , Exploratory Behavior/physiology , Helplessness, Learned , Hippocampus/ultrastructure , Immunohistochemistry , Intracellular Signaling Peptides and Proteins/metabolism , Male , Membrane Proteins/metabolism , Neurofilament Proteins/metabolism , Neurogenesis , Neuronal Plasticity/physiology , Neurons/metabolism , Neurons/ultrastructure , Rats , Rats, Wistar , Synapses/ultrastructure , Synaptic Transmission/physiology , Synaptophysin/metabolism , Tubulin/metabolismABSTRACT
Classical actions of the neurotrophin family are related to cellular survival and differentiation. Moreover, acute effects of neurotrophins have been reported. Although neurotrophins effects on synaptic transmission at central nervous system level have been largely studied, acute effects of neurotrophins on hypothalamic noradrenergic transmission are still poorly understood. Thus, we have studied the effects of the neurotrophin family members nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) on norepinephrine (NE) neuronal uptake and its evoked release, as well as the receptor and the intracellular pathways involved in these processes in rat hypothalamus. Present results indicate that BDNF increased NE uptake and decreased its evoked release through a mechanism that involve Trk B receptor and phospholipase C. Moreover, NT-4, also through the Trk B receptor, decreased NE uptake and its evoked release by activating phosphatidylinositol 3-OH-kinase. These effects were observed in whole hypothalamus as well as in the anterior hypothalamic zone. On the other hand, NGF did not modify noradrenergic transmission. In conclusion, we showed for the first time that BDNF and NT-4 activate two different intracellular signalling pathways through a Trk B receptor dependent mechanism. Furthermore, present findings support the hypothesis that BDNF and NT-4 acutely applied, could be considered as modulators of noradrenergic transmission and thus may regulate hypothalamic physiological as well as pathophysiological responses.
