With continued debate over the functional significance of adult neurogenesis, identifying an in vivo correlate of neurogenesis has become an important goal. Here we rely on the coupling between neurogenesis and angiogenesis and test whether MRI measurements of cerebral blood volume (CBV) provide an imaging correlate of neurogenesis. First, we used an MRI approach to generate CBV maps over time in the hippocampal formation of exercising mice. Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus CBV, the only subregion that supports adult neurogenesis. Moreover, exercise-induced increases in dentate gyrus CBV were found to correlate with postmortem measurements of neurogenesis. Second, using similar MRI technologies, we generated CBV maps over time in the hippocampal formation of exercising humans. As in mice, exercise was found to have a primary effect on dentate gyrus CBV, and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging.hippocampus ͉ in vivo imaging ͉ cerebral blood volume ͉ angiogenesis T he hippocampal formation, a brain circuit made up of separate but interconnected subregions (1), is vital for memory function (2) and is targeted by the aging process (3). The dentate gyrus is the only hippocampal subregion that supports neurogenesis in the adult brain (4-6). Nevertheless, because neurogenesis can only be assessed in postmortem tissue, its functional significance remains undetermined. With this limitation in mind, we have explored different imaging approaches applicable to rodents and humans that might provide an in vivo correlate of neurogenesis.Although imaging radioligands designed to bind newly dividing cells is an attractive approach, positron emission tomography imaging suffers inherently poor resolution and cannot visualize the dentate gyrus. Additionally, radiolabeling newborn cells introduces potential safety concerns. For these reasons, we have focused on MRI technologies instead. Notably, a coupling has been established between neurogenesis and angiogenesis (7,8). The process of angiogenesis, in turn, gradually gives rise to the formation of new blood vessels, increasing regional microvascular density (9-12). Importantly, vascular density can be measured in vivo with imaging techniques that map regional blood volume. Numerous studies have established a tight relationship between angiogenesis and regional blood volume (13-17), including in the brain where regional angiogenesis is coupled to regional cerebral blood volume (CBV) (18)(19)(20)(21)(22)(23)(24)(25)(26).Because CBV can be measured with MRI, we hypothesized that a regionally selective increase in hippocampal CBV might provide an imaging correlate of neurogenesis. This hypothesis was tested in...
Summary Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2+/- ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2+/ mice, but not in Atg7CKO neuronal autophagy deficient mice or Tsc2+/-:Atg7CKO double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR.
Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-β protein (Aβ) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Aβ- and Ca2+-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Aβ- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Aβ-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.
Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.
Synaptic dysfunction and the loss of synapses are early pathological features of Alzheimer's disease (AD). Synapses are sites of high energy demand and extensive calcium fluctuations; accordingly, synaptic transmission requires high levels of ATP and constant calcium fluctuation. Thus, synaptic mitochondria are vital for maintenance of synaptic function and transmission through normal mitochondrial energy metabolism, distribution and trafficking, and through synaptic calcium modulation. To date, there has been no extensive analysis of alterations in synaptic mitochondria associated with amyloid pathology in an amyloid β (Aβ)-rich milieu. Here, we identified differences in mitochondrial properties and function of synaptic vs. nonsynaptic mitochondrial populations in the transgenic mouse brain, which overexpresses the human mutant form of amyloid precursor protein and Aβ. Compared with nonsynaptic mitochondria, synaptic mitochondria showed a greater degree of agedependent accumulation of Aβ and mitochondrial alterations. The synaptic mitochondrial pool of Aβ was detected at an age as young as 4 mo, well before the onset of nonsynaptic mitochondrial and extensive extracellular Aβ accumulation. Aβ-insulted synaptic mitochondria revealed early deficits in mitochondrial function, as shown by increased mitochondrial permeability transition, decline in both respiratory function and activity of cytochrome c oxidase, and increased mitochondrial oxidative stress. Furthermore, a low concentration of Aβ (200 nM) significantly interfered with mitochondrial distribution and trafficking in axons. These results demonstrate that synaptic mitochondria, especially Aβ-rich synaptic mitochondria, are more susceptible to Aβ-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction relevant to the development of synaptic degeneration in AD.synaptic AB | mitochondrial trafficking | mitochondrial oxidative stress | mitochondrial dysfunction | synaptic injury B rain mitochondria are a mixture of synaptic and nonsynaptic mitochondria. Synaptic mitochondria differ from nonsynaptic mitochondria in size, motility, life span, and other properties. Synaptic mitochondria are energy warehouses that sustain the activity of neurons/synapses (1, 2). Synaptic mitochondria are synthesized in neuronal soma; they are then transported to nerve terminals (dendrites and axons), are distributed abundantly around synapses where mitochondria modulate calcium balance (3), and actively provide energy to fuel the synaptic function (4, 5). Synaptic mitochondria thus undergo constant activation to maintain synaptic function. Defects in synaptic mitochondria obviously compromise synaptic function (1, 6, 7), and synaptic mitochondria are vulnerable to accumulative damages. Multiple studies have shown that synaptic mitochondria undergo increased oxidation during aging (8, 9). In addition, synaptic mitochondria demonstrate higher levels of cyclophilin D (CypD), and are thereby more susceptible to calcium insult (10, 11). Given the impor...
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