Amplifying mitochondrial function rescues adult neurogenesis in a mouse model of Alzheimer's disease.

Adult hippocampal neurogenesis is strongly impaired in Alzheimer's disease (AD). In several mouse models of AD, it was shown that adult-born neurons exhibit reduced survival and altered synaptic integration due to a severe lack of dendritic spines. In the present work, using the APPxPS1 mouse model of AD, we reveal that this reduced number of spines is concomitant of a marked deficit in their neuronal mitochondrial content. Remarkably, we show that targeting the overexpression of the pro-neural transcription factor Neurod1 into APPxPS1 adult-born neurons restores not only their dendritic spine density, but also their mitochondrial content and the proportion of spines associated with mitochondria. Using primary neurons, a bona fide model of neuronal maturation, we identified that increases of mitochondrial respiration accompany the stimulating effect of Neurod1 overexpression on dendritic growth and spine formation. Reciprocally, pharmacologically impairing mitochondria prevented Neurod1-dependent trophic effects. Thus, since overexpression of Neurod1 into new neurons of APPxPS1 mice rescues spatial memory, our present data suggest that manipulating the mitochondrial system of adult-born hippocampal neurons provides neuronal plasticity to the AD brain. These findings open new avenues for far-reaching therapeutic implications towards neurodegenerative diseases associated with cognitive impairment.

Mechanism of elevated LH/FSH ratio in lean PCOS revisited: a path analysis.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-20% of reproductive-age women. However, the treatment of PCOS is mainly based on symptoms and not on its pathophysiology. Neuroendocrine disturbance, as shown by an elevated LH/FSH ratio in PCOS patients, was thought to be the central mechanism of the syndrome, especially in lean PCOS. LH and FSH secretion are influenced by GnRH pulsatility of GnRH neurons in the hypothalamus. Kisspeptin is the main regulator of GnRH secretion, whereas neurokinin B (NKB) and dynorphin regulate kisspeptin secretion in KNDy neurons. This study aims to deepen the understanding of the neuroendocrine disorder in lean PCOS patients and its potential pathophysiology-based therapy. A cross-sectional study was performed at Dr. Cipto Mangunkusumo Kencana Hospital and the IMERI UI HRIFP cluster with 110 lean PCOS patients as subjects. LH, FSH, LH/FSH ratio, kisspeptin, NKB, dynorphin, leptin, adiponectin, AMH, fasting blood glucose, fasting insulin, HOMA-IR, testosterone, and SHBG were measured. Bivariate and path analyses were performed to determine the relationship between variables. There was a negative association between dynorphin and kisspeptin, while NKB levels were not associated with kisspeptin. There was no direct association between kisspeptin and the LH/FSH ratio; interestingly, dynorphin was positively associated with the LH/FSH ratio in both bivariate and pathway analyses. AMH was positively correlated with the LH/FSH ratio in both analyses. Path analysis showed an association between dynorphin and kisspeptin levels in lean PCOS, while NKB was not correlated with kisspeptin. Furthermore, there was a correlation between AMH and the LH/FSH ratio, but kisspeptin levels did not show a direct significant relationship with the LH/FSH ratio. HOMA-IR was negatively associated with adiponectin levels and positively associated with leptin and FAI levels. In conclusion, AMH positively correlates with FAI levels and is directly associated with the LH/FSH ratio, showing its important role in neuroendocrinology in lean PCOS. From the path analysis, AMH was also an intermediary variable between HOMA-IR and FAI with the LH/FSH ratio. Interestingly, this study found a direct positive correlation between dynorphin and the LH/FSH ratio, while no association between kisspeptin and the LH/FSH ratio was found. Further research is needed to investigate AMH and dynorphin as potential therapeutic targets in the management of lean PCOS patients.

Mitochondrial OPA1 Deficiency Is Associated to Reversible Defects in Spatial Memory Related to Adult Neurogenesis in Mice.

Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated postmitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondria and in their dynamics appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, because of haploinsufficiency in the mitochondrial optic atrophy type 1 (OPA1) protein involved in mitochondrial dynamics. In males, we evaluated adult hippocampal neurogenesis parameters using immunohistochemistry. We performed a battery of tests to assess basal behavioral characteristics and cognitive performances, and tested putative treatments. While in dominant optic atrophy (DOA) mouse models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected adult-born hippocampal neurons showed a decrease in mitochondrial content. Remarkably, voluntary exercise or pharmacological treatment targeting mitochondrial dynamics restored spatial memory in DOA mice. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, amplification of mitochondrial function at an early stage appears beneficial for late-onset neurodegenerative diseases.

Protective Effect of High-Intensity Interval Training (HIIT) and Moderate-Intensity Continuous Training (MICT) against Vascular Dysfunction in Hyperglycemic Rats.

Background: Hyperglycemia is a major risk factor for endothelial dysfunction. Endothelial dysfunction is associated with the inability of endothelial cells to maintain homeostasis of the cardiovascular system. Regular exercise may be considered as an effective and low-cost nonpharmacological tool for improving vascular function, though there is no agreement on the best type of exercise. Objectives: To determine how high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) may prevent endothelial dysfunction under hyperglycemic conditions, and to compare these two interventions. Method: Twenty-four eight-week-old male Wistar rats were randomly assigned into four groups: healthy nonexercising control (C), hyperglycemic control (HG-C), hyperglycemic + HIIT (HG-IT), and hyperglycemic + MICT (HG-CT). Hyperglycemia was induced by a single injection of streptozotocin. Hyperglycemic animals were subjected to HIIT or MICT protocols six days a week for six weeks. Decapitation was performed the day after the exercise protocols were completed. The ascending aorta (until the abdominal artery) was examined. An enzyme-linked immunosorbent assay (ELISA) was used to measure the glucagon-likepeptide-1 (GLP-1), endothelial nitric oxide synthase (eNOS), and tumor necrosis factor-alpha (TNFα) levels. A colorimetric assay was used to measure superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. Quantitative real-time polymerase chain reaction (PCR) was used to measure the expression of the receptor for advanced glycation end-products (RAGE) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Hematoxylin and eosin (H&E) staining was used to histologically analyze the aortas. Results: There was a significantly higher level of GLP-1 and lower expression of RAGE, NF-κB, and TNFα in the HG-IT and HG-CT group compared to the HG-C group. Microscopic examination of aortic tissue showed a better tissue arrangement in both treatment groups than in the HG-C group. Except for the MDA level, there were no significant differences in any of the measured parameters between the HG-IT and HG-CT groups. Conclusion: Under hyperglycemic conditions, both HIIT and MICT have a protective role against endothelial dysfunction.

Mitochondria in Developmental and Adult Neurogenesis.

Generation of new neurons is a tightly regulated process that involves several intrinsic and extrinsic factors. Among them, a metabolic switch from glycolysis to oxidative phosphorylation, together with mitochondrial remodeling, has emerged as crucial actors of neurogenesis. However, although accumulating data raise the importance of mitochondrial morphology and function in neural stem cell proliferation and differentiation during development, information regarding the contribution of mitochondria to adult neurogenesis processes remains limited. In the present review, we discuss recent evidence covering the importance of mitochondrial morphology, function, and energy metabolism in the regulation of neuronal development and adult neurogenesis, and their impact on memory processes.

Memory formation orchestrates the wiring of adult-born hippocampal neurons into brain circuits.

During memory formation, structural rearrangements of dendritic spines provide a mean to durably modulate synaptic connectivity within neuronal networks. New neurons generated throughout the adult life in the dentate gyrus of the hippocampus contribute to learning and memory. As these neurons become incorporated into the network, they generate huge numbers of new connections that modify hippocampal circuitry and functioning. However, it is yet unclear as to how the dynamic process of memory formation influences their synaptic integration into neuronal circuits. New memories are established according to a multistep process during which new information is first acquired and then consolidated to form a stable memory trace. Upon recall, memory is transiently destabilized and vulnerable to modification. Using contextual fear conditioning, we found that learning was associated with an acceleration of dendritic spines formation of adult-born neurons, and that spine connectivity becomes strengthened after memory consolidation. Moreover, we observed that afferent connectivity onto adult-born neurons is enhanced after memory retrieval, while extinction training induces a change of spine shapes. Together, these findings reveal that the neuronal activity supporting memory processes strongly influences the structural dendritic integration of adult-born neurons into pre-existing neuronal circuits. Such change of afferent connectivity is likely to impact the overall wiring of hippocampal network, and consequently, to regulate hippocampal function.