The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.

Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.

Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall.

Exercise promotes learning and memory recall as well as rescues cognitive decline associated with aging. The positive effects of exercise are mediated by circulatory factors that predominantly increase Brain Derived Neurotrophic Factor (BDNF) signaling in the hippocampus. Identifying the pathways that regulate the release of the circulatory factors by various tissues during exercise and that mediate hippocampal Mus musculus Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that two weeks of voluntary exercise in male mice activates autophagy in the hippocampus by increasing LC3B protein levels (p = 0.0425) and that autophagy is necessary for exercise-induced spatial learning and memory retention (p < 0.001; exercise + autophagy inhibitor chloroquine CQ versus exercise). We place autophagy downstream of hippocampal BDNF signaling and identify a positive feedback activation between the pathways. We also assess whether the modulation of autophagy outside the nervous system is involved in mediating exercise's effect on learning and memory recall. Indeed, plasma collected from young exercise mice promote spatial learning (p = 0.0446; exercise versus sedentary plasma) and memory retention in aged inactive mice (p = 0.0303; exercise versus sedentary plasma), whereas plasma collected from young exercise mice that received the autophagy inhibitor chloroquine diphosphate failed to do so. We show that the release of exercise factors that reverse the symptoms of aging into the circulation is dependent on the activation of autophagy in young animals. Indeed, we show that the release of the exercise factor, beta-hydroxybutyrate (DBHB), into the circulation, is autophagy-dependent and that DBHB promotes spatial learning and memory formation (p = 0.0005) by inducing hippocampal autophagy (p = 0.0479). These results implicate autophagy in peripheral tissues and in the hippocampus in mediating the effects of exercise on learning and memory recall and identify DBHB as a candidate endogenous exercise factor whose release and positive effects are autophagy-dependent.

Methionine mediates resilience to chronic social defeat stress by epigenetic regulation of NMDA receptor subunit expression.

RATIONALE: Previous studies suggested that methionine (Met) levels are decreased in depressed patients. However, whether the decrease in this amino acid is important for phenotypic behaviors associated with depression has not been deciphered. OBJECTIVE: The response of individuals to chronic stress is variable, with some individuals developing depression and others becoming resilient to stress. In this study, our objective was to examine the effect of Met on susceptibility to stress. METHODS: Male C57BL/6J mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day 11, the behavior of mice was assessed using social interaction and open-field tests. Mice received Met 4 h before each defeat session. Epigenetic targets were assessed either through real-rime RTPCR or through Western Blots. RESULTS: Met did not modulate anxiety-like behaviors, but rather promoted resilience to chronic stress, rescued social avoidance behaviors and reversed the increase in the cortical expression levels of N-methyl-D-aspartate receptor (NMDAR) subunits. Activating NMDAR activity abolished the ability of Met to promote resilience to stress and to rescue social avoidance behavior, whereas inhibiting NMDAR did not show any synergistic or additive protective effects. Indeed, Met increased the cortical levels of the histone methyltransferase SETDB1, and in turn, the levels of the repressive histone H3 lysine (K9) trimethylation (me3). CONCLUSIONS: Our data indicate that Met rescues susceptibility to stress by inactivating cortical NMDAR activity through an epigenetic mechanism involving histone methylation.

Nicotine induces resilience to chronic social defeat stress in a mouse model of water pipe tobacco exposure by activating BDNF signaling.

The purpose of this study was to investigate how nicotine in the context of water pipe tobacco smoking (WTS) affects depression and anxiety-like behaviors associated with chronic social defeat stress (CSDS). Male C57BL/6 J mice were exposed to WTS or received intraperitoneal injections of nicotine for thirty days then subjected to CSDS for ten days. During CSDS, mice were exposed to WTS or received nicotine injections. The social interaction and open-field tests were used to classify animals as resilient or susceptible to stress and to evaluate their anxiety-like behavior. After behavioral testing, mice continued to be exposed to WTS/nicotine for ten days and their behavior was reexamined. The involvement of brain derived neurotrophic factor signaling in the nicotine-mediated effects was assessed with the tropomyosin receptor kinase B (TRKB) inhibitor, ANA-12. We found that WTS promotes resilience to stress and rescues social avoidance. Even though WTS initially decreased anxiety-like behaviors, prolonged exposure after the completion of CSDS significantly induced anxiety-like behaviors. Finally, we showed that nicotine mediates the effects of WTS only on resilience to stress by increasing BDNF and TRKB levels and signaling. Our results suggest that the pathways mediating resilience to stress and anxiety are distinct and that nicotine mediates the effects of WTS on social behavior, but not anxiety, by activating BDNF signaling. Significance statement: This study reports the positive effect of WTS and nicotine on social behavior. Furthermore, it shows the negative effects of prolonged WTS on anxiety-like behaviors and suggests that these effects are not necessarily mediated by nicotine. Finally, it identifies BDNF/TRKB signaling pathway as a major mediator of the positive effects of nicotine on social interaction. As a result, this work emphasizes the importance of considering the activation status of this signaling pathway when developing smoking cessation strategies.

Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF/TRKB signaling.

How individuals respond to chronic stress varies. Susceptible individuals ultimately develop depression; whereas resilient individuals live normally. In this study, our objective was to examine the effect of branched-chain amino acids (BCAA), commonly used by athletes, on susceptibility to stress. Male C57BL/6 mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day11, the behavior of mice was assessed using the social interaction test, elevated plus maze and open field. Mice received the BCAA leucine, isoleucine or valine before each defeat session. Furthermore, we examined whether BCAA regulate brain derived neurotrophic factor (BDNF) signaling by using a brain-permeable tropomyosin receptor kinase B (TRKB) inhibitor, ANA-12. We also tested the effect of voluntary exercise and high protein diets on susceptibility to stress. Mice exposed to chronic stress displayed increased susceptibility and social avoidance. BCAA promoted resilience to chronic stress, rescued social avoidance behaviors and increased hippocampal BDNF levels and TRKB activation. Inhibition of TRKB signaling abolished the ability of BCAA to promote resilience to stress and to rescue social avoidance. Interestingly, we found that BCAA activate the exercise-regulated PGC1a/FNDC5 pathway known to induce hippocampal BDNF signaling. Although both voluntary exercise and BCAA promoted resilience to stress, combining them did not yield synergistic effects confirming that they affect similar pathways. We also discovered that high protein diets mimic the effect of BCAA by rescuing social deficits induced by chronic stress and increase Bdnf expression in the hippocampus. Our data indicate that BCAA, exercise and high protein diets rescue susceptibility to stress by activating the hippocampal BDNF/TRKB signaling.

Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF).

Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.SIGNIFICANCE STATEMENT It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."

Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases.

Chronic stress promotes depression in some individuals, but has no effect in others. Susceptible individuals exhibit social avoidance and anxious behavior and ultimately develop depression, whereas resilient individuals live normally. Exercise counteracts the effects of stress. Our objective was to examine whether lactate, a metabolite produced during exercise and known to reproduce specific brain exercise-related changes, promotes resilience to stress and acts as an antidepressant. To determine whether lactate promotes resilience to stress, male C57BL/6 mice experienced daily defeat by a CD-1 aggressor, for 10 days. On the 11th day, mice were subjected to behavioral tests. Mice received lactate before each defeat session. When compared with control mice, mice exposed to stress displayed increased susceptibility, social avoidance and anxiety. Lactate promoted resilience to stress and rescued social avoidance and anxiety by restoring hippocampal class I histone deacetylase (HDAC) levels and activity, specifically HDAC2/3. To determine whether lactate is an antidepressant, mice only received lactate from days 12-25 and a second set of behavioral tests was conducted on day 26. In this paradigm, we examined whether lactate functions by regulating HDACs using co-treatment with CI-994, a brain-permeable class I HDAC inhibitor. When administered after the establishment of depression, lactate behaved as antidepressant. In this paradigm, lactate regulated HDAC5 and not HDAC2/3 levels. On the contrary, HDAC2/3 inhibition was antidepressant-like. This indicates that lactate mimics exercise's effects and rescues susceptibility to stress by modulating HDAC2/3 activity and suggests that HDAC2/3 play opposite roles before and after establishment of susceptibility to stress.