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Nutrients and neurogenesis: the emerging role of autophagy and gut microbiota
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ScienceDirect Nutrients and neurogenesis: the emerging role of autophagy and gut microbiota Virve Cavallucci1,2, Marco Fidaleo1,2 and Giovambattista Pani1,2 Adult neurogenesis, the generation of mature functional neurons from neural stem cells in specific regions of the adult mammalian brain, is implicated in brain physiology, neurodegeneration and mood disorders. Among the many intrinsic and extrinsic factors that modulate neurogenic activity, the role of nutrients, energy metabolism, and gut microbiota has recently emerged. It is increasingly evident that excessive calorie intake accelerates the age-dependent decline of neurogenesis, while calorie restriction and physical exercise have the opposite effect. Mechanistically, nutrient availability could affect neurogenesis by modulating autophagy, a cellrejuvenating process, in neural stem cells. In parallel, diet can alter the composition of gut microbiota thus impacting the intestine-neurogenic niche communication. These exciting breakthroughs are here concisely reviewed. Addresses 1 Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy 2 Institute of General Pathology, Universita` Cattolica del Sacro Cuore, Roma, Italy Corresponding authors: Cavallucci, Virve ([email protected]), Pani, Giovambattista ([email protected])
Current Opinion in Pharmacology 2020, 50:46–52 This review comes from a themed issue on Neurosciences: neurogenesis Edited by Annalisa Buffo and Stefania Ceruti
https://doi.org/10.1016/j.coph.2019.11.004 1471-4892/ã 2019 Elsevier Ltd. All rights reserved.
Introduction Neurogenesis is the generation of new neurons in the brain that occurs by the division of neural stem cells (NSC) and subsequent maturation in neural progenitor cells (NPC) and then into neurons [1]. Understandably neurogenesis plays a crucial role during embryonic development for the construction of the nervous system (embryonic neurogenesis) but it is now clearly established that it continues even during adult life in some region of the mammalian brain (adult neurogenesis). The main well-documented neurogenic areas of the adult brain are the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus where new granule cells Current Opinion in Pharmacology 2020, 50:46–52
originate, and the subventricular zone (SVZ) of the lateral ventricles where new olfactory bulb (OB) interneurons are generated. Adult neurogenesis also occurs in other brain regions such as the hypothalamus. Unlike during embryonic development, neurogenesis proceeds in the adult brain at a slow rate since adult NSC (aNSC) are mainly quiescent. Once activated, aNSC principally divide asymmetrically to generate another NSC (self-renewal) and a transit-amplifying cell (TAC), the latter representative of a pluripotent and highly proliferative state. It is however possible, as recently demonstrated in the SVZ of the adult mouse brain, that the generation of differentiated neurons occurs without depletion of stem cell pool through the symmetric division of NSC generating either two self-renewing or two differentiating daughter cells [2]. Neurogenesis declines with brain aging and in neurodegenerative disorders while is induced by different types of central nervous system (CNS) damage, including ischemic, mechanical and excitotoxic injury, indicating a role in tissue repair and cell replacement after brain damage [3]. In addition to brain repair, adult neurogenesis also plays a more functional role. In fact, the generation of new OB interneurons and their correct elimination are required for several olfactory behaviors such as odor detection and discrimination, and the retention of olfactory memory [4]. In the hippocampus, a brain region primarily associated with memory, increased neurogenesis is associated with improved behavioral performance, whereas reduced neurogenesis causes cognitive impairment [5]. Moreover, voluntary physical exercise as running promotes both neurogenesis and learning and memory [6]. In the hypothalamus, where tanycytes (the hypothalamic stem cells) are in a privileged position to receive nutrition-related signals, neurogenesis is involved in body weight homeostasis and in energy balance control [7]. Neurogenesis is indeed strongly influenced by the nutrients and growth factors supplied by the vasculature. Accordingly, neurogenic niches present characteristic vascular plexi that allows the NSC to come into contact with the molecules and nutrients carried by blood circulation [8]. Adult neurogenesis is regulated by different intrinsic factors, as inflammatory cytokines, neurotransmitters, hormones and neurotrophic factors, and by extrinsic www.sciencedirect.com
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factors like physical activity and dietary intake. Here we highlight the importance of diet and the emerging role of nutrient-regulated process and of the gut-brain axis in the modulation of adult neurogenesis (see Figure 1).
The role of energy metabolism on neurogenesis: mind the fuel gauge Environmental factors are strongly involved in the regulation of neurogenesis. Among these, food intake, and therefore energy metabolism, plays a crucial role in NSC fate decision. Neurogenic niches are characterized by low oxygen tension and, not by chance, an elevated anaerobic glycolytic activity is associated with neural stemness. During differentiation, instead, oxidative phosphorylation becomes predominant [9,10]. Adult hippocampal neurogenic lineage is strongly dependent on the mitochondrial
electron transport chain and oxidative phosphorylation during the fast proliferating progenitor cell phase and the disruption of mitochondrial function inhibits neurogenesis at NPC stage and reproduces aging-like phenotypes [11]. Also the fatty acid (FA) metabolism is involved in NSC fate decision during adult neurogenesis. The rate of FA oxidation (FAO) regulates the activity of NSC and a metabolic shift in FAO regulates the proliferation of NSC/NPC. To note, manipulation of malonyl-CoA (the metabolite that regulates FAO levels) induces exit from quiescence and enhances NSC/NPC proliferation [12]. In a mouse model of Alzheimer’s Disease (3xTg-AD) NSC impairment correlates with lipid accumulation in SVZ indicating that diseaseinduced perturbation of niche fatty acid metabolism destroys the homeostatic and regenerative capacity of NSC [13]. Interestingly, the same authors found similar
Figure 1
Physical exercice
Adult neurogenesis
Autophagy
Gut microbiota Antibiotics Current Opinion in Pharmacology
Adult neurogenesis is controlled by different factors including physical exercise and autophagy. The latter can be modulated, among other stimuli, by food intake and nutrients availability. High calorie diet negatively influences adult neurogenesis while calorie restriction improves it. Diet, and other factors as antibiotics administration, can influence the gut microbiota composition and this, in turn, has an effect on adult neurogenesis and brain function. Red arrows: negative effects; green arrows: positive effects; blue arrows: involvement in the regulation. (The image representing autophagy is modified from the photo by the Nobel Assembly at the Karolinska Institute).
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lipid accumulations in the SVZ of postmortem human AD brains. Reducing calorie intake in rodents counteracts age-related cognitive decline, increases the newly generated neurons in the SGZ and the levels of brain-derived neurotrophic factor (BDNF) [14]. Moreover, calorie restriction prevents the age-related loss of neurogenesis in SVZ, enhances olfactory memory and reduces the age-dependent activation of inflammatory processes [15]. Conversely, adult neurogenesis is compromised in animal models of diet-induced obesity and diabetes. High-fat diet (HFD) impairs hippocampal neurogenesis in rodents and reduces the levels of BDNF in the hippocampus [16,17]. In the arcuate nucleus (ArcN) of the hypothalamus, HFD causes an increase in newly generated anorexigenic (appetite-suppressing) neurons, suggesting that the newborn neuron maturation not only is regulated by nutrition, but also serves homeostatic functions in the maintenance of energy balance and avoidance of severe HFD-induced weight gain [18]. Consistent with the above evidence, diabetes, a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of cognitive impairment, reportedly inhibits adult neurogenesis at different steps (proliferation, differentiation and cell survival). High glucose levels in vitro abolish NSC differentiation through oxidative stress and oxidative stress-induced ER stress [19]. Moreover, excessive glucose levels cause an impairment of NSC self-renewal capacity through a molecular circuit involving the transcription factor CREB and Sirtuin 1 [20]. In spite of these intriguing evidence, however, the relative importance of impaired neurogenesis (as opposed to other mechanisms including vascular damage and direct injury to mature neurons and their connectivity) for diabetes’detrimental impact on neurocognitive functions and on brain ageing remains to be fully established. Beside affecting neurogenesis through energy balance and related pathologies such as obesity and diabetes, nutrition may modulate both embryonic and adult neurogenesis via the supply of key micronutrients and oligo-elements. Among those, early life iron deficiency has been recognized to have deleterious long-term effects on hippocampusdependent learning and memory, in a fashion that may involve impaired CREB-mediated gene expression [21]. More directly related to neurogenic mechanisms, mice deficient of the iron trafficking protein Lipocalin 2 display deficits in NSC proliferation and commitment, paralleled by reduced performance in the hippocampal-dependent contextual fear discriminative tasks [22]. Conversely, mice in which iron sensing in NPC has been decreased by conditional deletion of the ubiquitin ligase FBXL5 present NPC hyperproliferation and enhanced gliogenesis as the result of iron overload, which in turn leads to increased levels of intracellular reactive oxygen species and activation Current Opinion in Pharmacology 2020, 50:46–52
of the nutrient sensor mTOR [23]. While these studies highlight a crucial role for intracellular (and systemic) iron levels in neurogenic processes, further studies are warranted to determine whether and to which extent adult neurogenesis can be affected by clinically relevant conditions of iron nutritional deficiency or overload. Although the role of diet-derived vitamins in neurogenesis has so far remained relatively investigated, both vitamin C (Ascorbic Acid) and vitamin D supplementation has proven effective in boosting neurogenesis and preserving cognition in mouse models of neurodegeneration and brain ageing [24,25]. Moreover, retinoic acid (RA), an active derivative of vitamin A, appears to be crucial for early neurogenesis in the developing mouse cerebral cortex. Indeed, where perturbed, RA metabolism leads to premature neuronal differentiation of radial glia, reduced cortical cellularity and microcephaly [26]. Interestingly, both vitamin D and RA exert their action through a nuclear receptors family engaging extensive molecular and functional crosstalks with each other and with PPARs, the latter a class of transcriptional regulators whose relevance in the metabolic and nutritional regulation of NSC fate is increasingly recognized [27,28]. The emerging proneurogenic action of other micro/macro nutrients, such as food-derived polyphenols and poly unsaturated fatty acids (PUFA), together with their known or presumed mechanisms of action, has been recently reviewed [29].
Autophagy: how famine in the niche helps brain rejuvenation Autophagy (from Greek ‘self-eating’) is an evolutionarily conserved process for the degradation and recycling of cellular components. The best-characterized form of autophagy, macroautophagy (hereafter referred to as autophagy), is the main catabolic mechanism of eukaryotic cells to ensure quality control of the organelles and to maintain nutrient homeostasis. It is regulated by a set of autophagy-related (Atg) proteins involved in doublemembrane vesicles (autophagosomes) formation, maturation and fusion with lysosomes (for a review on autophagy see Ref. [30]). Autophagy can be induced by different stress conditions including nutrient deprivation. One of the key regulators of this process is the mammalian target of rapamycin (mTOR) that inhibits autophagy in the presence of growth factors and nutrients availability. Conversely, the energy sensor AMP-activated protein kinase (AMPK) that responds to AMP accumulation caused by ATP depletion promotes autophagy [31]. Autophagy is involved in various cellular functions and in different pathological and physiological processes. Among these, autophagy has a role in the regulation of stem cells (for review see Ref. [32] and it is required for neurodevelopment and embryonic neurogenesis. In the www.sciencedirect.com
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last years a role of autophagy in adult neurogenesis has also been demonstrated. For example, the pro-autophagic proteins Ambra1 and Beclin1 are highly expressed in the adult mouse SVZ and their downregulation causes a reduction of NSC proliferation and an increase of apoptosis [33]. In the hippocampus autophagy is active in the progeny of the adult NPC and Atg5 is required for their survival, as well as being involved in running-induced hippocampal neurogenesis [34]. Forkhead box O (FoxO) proteins are a highly conserved family of insulin-regulated and growth factor-regulated transcription factors controlling the expression of genes involved in several cell functions, including autophagy. Interestingly, it has been demonstrated that FoxO transcription factors are required to maintain autophagic turnover in adult NSC and NPC and that FoxO-dependent autophagy is necessary for maturation and integration of adult-born hippocampal neurons [35,36]. Moreover, pharmacological induction of autophagy is able to rescue FoxO deficiency-associated morphogenic deficits such as altered dendritic morphology and spine density [35]. The exquisite responsiveness to metabolic and hormonal signals related to the quality/quantity of food intake and the mechanistic link with stem cell function make of autophagy a potential key player in the nutritional modulation of neurogenesis and brain health; however, the relevance of this process in neurogenesis impairment in the context of metabolic disease or vice versa in neurogenic response to calorie restriction or physical exercise, remains to be fully demonstrated.
Gut microbiota, a connection between nutrition and neurogenesis? The gut microbiota, the microorganism community that resides in the gastrointestinal tract, regulates nutrition and metabolism and plays a fundamental role in many host processes including brain development and function [37]. Alterations in the gut microbiota-brain axis have been associated with neurodevelopmental disorders (e.g. autism), stress-related disorders such as depression and anxiety, and cognitive functions [38]. For example, the disruption of colon bacterial community by short-term intragastric treatment of adult mice with antibiotics causes cognitive impairment [39]. Ogbonnaya et al. [40] used germ-free (GF) mice (i.e. animals that have never been exposed to microorganisms) to investigate the involvement of microbiota in neurogenesis. They observed that GF mice have increased neurogenesis in the dorsal hippocampus compared to control (conventionally germ-colonized) mice, and that postweaning microbial colonization has no effect on these differences. They suggest the existence of a ‘window’ period during postnatal development in which microbial colonization can influence adult hippocampal neurogenesis [40]. Nevertheless, the relevance of these yet www.sciencedirect.com
intriguing observations is weakened by the limitations of the GF model, in which several behavioral and brain structure alterations have been reported [41]. In contrast, adult mice subdued to long-term antibiotic treatment so as to deplete gut microbiota, present reduced hippocampal neurogenesis and impaired cognitive function. Probiotic administration or voluntary exercise (running) is able to rescue these antibiotic-induced alterations and also to increase the numbers of Ly6Chi monocytes in the brain. Ly6Chi cells are murine monocytes that infiltrate inflammatory sites and can have context-dependent (beneficial or detrimental) effects in the CNS. 0 Disruption of Ly6Chi monocytes decreases neurogenesis, whereas the transfer of Ly6Chi monocytes rescues neurogenesis after antibiotic treatment, indicating that Ly6Chi monocytes may represent a link between antibiotic-induced alteration of gut microbiota and hippocampal neurogenic response [42]. As mentioned above, many recent studies suggest a strong link between the gut microbiota composition and the development of mental disorders such as depression and anxiety [43]. Along parallel lines of evidence, depression and anxiety have been found associated with an impairment of neurogenesis, while antidepressants stimulate neurogenesis in a fashion that mirrors their clinical efficacy, suggesting the idea that depression could be the result of an altered adult neurogenesis [10], and by extension that microbiota roles in mood disorders may be mechanistically mediated by an impaired neurogenic capacity. Adding to this intriguing view, it was shown already several years ago that antimicrobials-induced alterations of gut microbiota in mice increase exploratory behavior and hippocampal expression of BDNF [44], the latter a neurotrophin pivotal to neuronal growth and survival whose hippocampal levels are also elevated by chronic treatment with different classes of antidepressant drugs. Also of note, the expression of BDNF is increased in different brain regions (i.e. hippocampus, brainstem and hypothalamus) of GF mice [45]. Although in part conflicting, the above evidence clearly outlines a potential gut-brain axis sustained by the resident gut microflora and impacting on hippocampal neurogenesis and by extension on mood disorders. Although the mechanistic details of such circuitry remain to be clarified, BDNF may represent a distal effector, while microbial products, microbe-regulated retinoic acid synthesis [46–48] or microbe-primed inflammatory cells may represent more proximal triggers. Not least, the possibility that microbe effects on adult neurogenesis occur as indirect consequences of an altered systemic inflammatory and metabolic environment remains to be carefully considered [49,50].
Conclusions Unlike in animal model systems, whether adult neurogenesis occurs in humans and significantly contributes to brain function and disease is still a matter of debate [51,52]. Accordingly, very little information is available on the Current Opinion in Pharmacology 2020, 50:46–52
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impact of diet and nutrition/metabolism on postnatal neurogenesis even in its very early stages, and mostly based on (indirect) evidence from in vivo imaging studies on brain structures, or on immune-histochemical analysis of post mortem samples. Relevant to the present article, Page and Xiang reported that exposure to maternal obesity and diabetes during fetal development is associated in children with reduced hippocampal volume and impaired hypothalamic glucose responsiveness predictive of future weight gain [53,54]. Along a different line of investigation, Kafouri et al. found that duration of exclusive breastfeeding (as opposite to infant formula) is an important predictor of parietal cortical thickness (and of general intelligence) in adolescents [55]. However a direct link between these important observations with developmental (or early postnatal) neurogenesis is still missing. Intrauterine exposure to ethanol has devastating effects on brain development in the contest of the Fetal alcoholic spectrum disorder, suggesting that embryonic neurogenesis may represent a relevant target of alcoholic teratogenesis. Interestingly, Druig et al. reported solid immunohistochemical evidence of reduced hippocampal adult neurogenesis in the brain of individuals with a history of alcohol abuse [56]. Besides reflecting a direct toxic effect of ethanol on neural stem cells and progenitors, impaired neurogenesis may result from a compromised general nutritional status as it occurs in alcoholism. In conclusion, the Western lifestyle is increasingly characterized by excessive caloric intake and insufficient physical activity, two factors leading to different metabolic disorders which are a risk factor for cognitive impairment. The evidence that metabolism could play a crucial role in modulating adult neurogenesis, a process involved in brain physiology that helps to ‘keep the brain young’, should be a stimulus for the development of dietary (or pharmacological) interventions to improve neurogenic activity and delay its age-related deterioration.
Conflict of interest statement Nothing declared.
Acknowledgements Virve Cavallucci is supported by the Italian Ministry of Health (Young Researchers Grant GR-2016-02363179). Marco Fidaleo is supported by the Italian Ministry of Health (Young Researchers GR-2016-02364891). Giovambattista Pani is supported by Catholic University Intramural Grants D3.2 2015 and D1 2018. The authors are grateful to Dr. Renata Colavitti for critically reading and commenting the manuscript.
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ScienceDirect Nutrients and neurogenesis: the emerging role of autophagy and gut microbiota Virve Cavallucci1,2, Marco Fidaleo1,2 and Giovambattista Pani1,2 Adult neurogenesis, the generation of mature functional neurons from neural stem cells in specific regions of the adult mammalian brain, is implicated in brain physiology, neurodegeneration and mood disorders. Among the many intrinsic and extrinsic factors that modulate neurogenic activity, the role of nutrients, energy metabolism, and gut microbiota has recently emerged. It is increasingly evident that excessive calorie intake accelerates the age-dependent decline of neurogenesis, while calorie restriction and physical exercise have the opposite effect. Mechanistically, nutrient availability could affect neurogenesis by modulating autophagy, a cellrejuvenating process, in neural stem cells. In parallel, diet can alter the composition of gut microbiota thus impacting the intestine-neurogenic niche communication. These exciting breakthroughs are here concisely reviewed. Addresses 1 Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy 2 Institute of General Pathology, Universita` Cattolica del Sacro Cuore, Roma, Italy Corresponding authors: Cavallucci, Virve ([email protected]), Pani, Giovambattista ([email protected])
Current Opinion in Pharmacology 2020, 50:46–52 This review comes from a themed issue on Neurosciences: neurogenesis Edited by Annalisa Buffo and Stefania Ceruti
https://doi.org/10.1016/j.coph.2019.11.004 1471-4892/ã 2019 Elsevier Ltd. All rights reserved.
Introduction Neurogenesis is the generation of new neurons in the brain that occurs by the division of neural stem cells (NSC) and subsequent maturation in neural progenitor cells (NPC) and then into neurons [1]. Understandably neurogenesis plays a crucial role during embryonic development for the construction of the nervous system (embryonic neurogenesis) but it is now clearly established that it continues even during adult life in some region of the mammalian brain (adult neurogenesis). The main well-documented neurogenic areas of the adult brain are the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus where new granule cells Current Opinion in Pharmacology 2020, 50:46–52
originate, and the subventricular zone (SVZ) of the lateral ventricles where new olfactory bulb (OB) interneurons are generated. Adult neurogenesis also occurs in other brain regions such as the hypothalamus. Unlike during embryonic development, neurogenesis proceeds in the adult brain at a slow rate since adult NSC (aNSC) are mainly quiescent. Once activated, aNSC principally divide asymmetrically to generate another NSC (self-renewal) and a transit-amplifying cell (TAC), the latter representative of a pluripotent and highly proliferative state. It is however possible, as recently demonstrated in the SVZ of the adult mouse brain, that the generation of differentiated neurons occurs without depletion of stem cell pool through the symmetric division of NSC generating either two self-renewing or two differentiating daughter cells [2]. Neurogenesis declines with brain aging and in neurodegenerative disorders while is induced by different types of central nervous system (CNS) damage, including ischemic, mechanical and excitotoxic injury, indicating a role in tissue repair and cell replacement after brain damage [3]. In addition to brain repair, adult neurogenesis also plays a more functional role. In fact, the generation of new OB interneurons and their correct elimination are required for several olfactory behaviors such as odor detection and discrimination, and the retention of olfactory memory [4]. In the hippocampus, a brain region primarily associated with memory, increased neurogenesis is associated with improved behavioral performance, whereas reduced neurogenesis causes cognitive impairment [5]. Moreover, voluntary physical exercise as running promotes both neurogenesis and learning and memory [6]. In the hypothalamus, where tanycytes (the hypothalamic stem cells) are in a privileged position to receive nutrition-related signals, neurogenesis is involved in body weight homeostasis and in energy balance control [7]. Neurogenesis is indeed strongly influenced by the nutrients and growth factors supplied by the vasculature. Accordingly, neurogenic niches present characteristic vascular plexi that allows the NSC to come into contact with the molecules and nutrients carried by blood circulation [8]. Adult neurogenesis is regulated by different intrinsic factors, as inflammatory cytokines, neurotransmitters, hormones and neurotrophic factors, and by extrinsic www.sciencedirect.com
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factors like physical activity and dietary intake. Here we highlight the importance of diet and the emerging role of nutrient-regulated process and of the gut-brain axis in the modulation of adult neurogenesis (see Figure 1).
The role of energy metabolism on neurogenesis: mind the fuel gauge Environmental factors are strongly involved in the regulation of neurogenesis. Among these, food intake, and therefore energy metabolism, plays a crucial role in NSC fate decision. Neurogenic niches are characterized by low oxygen tension and, not by chance, an elevated anaerobic glycolytic activity is associated with neural stemness. During differentiation, instead, oxidative phosphorylation becomes predominant [9,10]. Adult hippocampal neurogenic lineage is strongly dependent on the mitochondrial
electron transport chain and oxidative phosphorylation during the fast proliferating progenitor cell phase and the disruption of mitochondrial function inhibits neurogenesis at NPC stage and reproduces aging-like phenotypes [11]. Also the fatty acid (FA) metabolism is involved in NSC fate decision during adult neurogenesis. The rate of FA oxidation (FAO) regulates the activity of NSC and a metabolic shift in FAO regulates the proliferation of NSC/NPC. To note, manipulation of malonyl-CoA (the metabolite that regulates FAO levels) induces exit from quiescence and enhances NSC/NPC proliferation [12]. In a mouse model of Alzheimer’s Disease (3xTg-AD) NSC impairment correlates with lipid accumulation in SVZ indicating that diseaseinduced perturbation of niche fatty acid metabolism destroys the homeostatic and regenerative capacity of NSC [13]. Interestingly, the same authors found similar
Figure 1
Physical exercice
Adult neurogenesis
Autophagy
Gut microbiota Antibiotics Current Opinion in Pharmacology
Adult neurogenesis is controlled by different factors including physical exercise and autophagy. The latter can be modulated, among other stimuli, by food intake and nutrients availability. High calorie diet negatively influences adult neurogenesis while calorie restriction improves it. Diet, and other factors as antibiotics administration, can influence the gut microbiota composition and this, in turn, has an effect on adult neurogenesis and brain function. Red arrows: negative effects; green arrows: positive effects; blue arrows: involvement in the regulation. (The image representing autophagy is modified from the photo by the Nobel Assembly at the Karolinska Institute).
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lipid accumulations in the SVZ of postmortem human AD brains. Reducing calorie intake in rodents counteracts age-related cognitive decline, increases the newly generated neurons in the SGZ and the levels of brain-derived neurotrophic factor (BDNF) [14]. Moreover, calorie restriction prevents the age-related loss of neurogenesis in SVZ, enhances olfactory memory and reduces the age-dependent activation of inflammatory processes [15]. Conversely, adult neurogenesis is compromised in animal models of diet-induced obesity and diabetes. High-fat diet (HFD) impairs hippocampal neurogenesis in rodents and reduces the levels of BDNF in the hippocampus [16,17]. In the arcuate nucleus (ArcN) of the hypothalamus, HFD causes an increase in newly generated anorexigenic (appetite-suppressing) neurons, suggesting that the newborn neuron maturation not only is regulated by nutrition, but also serves homeostatic functions in the maintenance of energy balance and avoidance of severe HFD-induced weight gain [18]. Consistent with the above evidence, diabetes, a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of cognitive impairment, reportedly inhibits adult neurogenesis at different steps (proliferation, differentiation and cell survival). High glucose levels in vitro abolish NSC differentiation through oxidative stress and oxidative stress-induced ER stress [19]. Moreover, excessive glucose levels cause an impairment of NSC self-renewal capacity through a molecular circuit involving the transcription factor CREB and Sirtuin 1 [20]. In spite of these intriguing evidence, however, the relative importance of impaired neurogenesis (as opposed to other mechanisms including vascular damage and direct injury to mature neurons and their connectivity) for diabetes’detrimental impact on neurocognitive functions and on brain ageing remains to be fully established. Beside affecting neurogenesis through energy balance and related pathologies such as obesity and diabetes, nutrition may modulate both embryonic and adult neurogenesis via the supply of key micronutrients and oligo-elements. Among those, early life iron deficiency has been recognized to have deleterious long-term effects on hippocampusdependent learning and memory, in a fashion that may involve impaired CREB-mediated gene expression [21]. More directly related to neurogenic mechanisms, mice deficient of the iron trafficking protein Lipocalin 2 display deficits in NSC proliferation and commitment, paralleled by reduced performance in the hippocampal-dependent contextual fear discriminative tasks [22]. Conversely, mice in which iron sensing in NPC has been decreased by conditional deletion of the ubiquitin ligase FBXL5 present NPC hyperproliferation and enhanced gliogenesis as the result of iron overload, which in turn leads to increased levels of intracellular reactive oxygen species and activation Current Opinion in Pharmacology 2020, 50:46–52
of the nutrient sensor mTOR [23]. While these studies highlight a crucial role for intracellular (and systemic) iron levels in neurogenic processes, further studies are warranted to determine whether and to which extent adult neurogenesis can be affected by clinically relevant conditions of iron nutritional deficiency or overload. Although the role of diet-derived vitamins in neurogenesis has so far remained relatively investigated, both vitamin C (Ascorbic Acid) and vitamin D supplementation has proven effective in boosting neurogenesis and preserving cognition in mouse models of neurodegeneration and brain ageing [24,25]. Moreover, retinoic acid (RA), an active derivative of vitamin A, appears to be crucial for early neurogenesis in the developing mouse cerebral cortex. Indeed, where perturbed, RA metabolism leads to premature neuronal differentiation of radial glia, reduced cortical cellularity and microcephaly [26]. Interestingly, both vitamin D and RA exert their action through a nuclear receptors family engaging extensive molecular and functional crosstalks with each other and with PPARs, the latter a class of transcriptional regulators whose relevance in the metabolic and nutritional regulation of NSC fate is increasingly recognized [27,28]. The emerging proneurogenic action of other micro/macro nutrients, such as food-derived polyphenols and poly unsaturated fatty acids (PUFA), together with their known or presumed mechanisms of action, has been recently reviewed [29].
Autophagy: how famine in the niche helps brain rejuvenation Autophagy (from Greek ‘self-eating’) is an evolutionarily conserved process for the degradation and recycling of cellular components. The best-characterized form of autophagy, macroautophagy (hereafter referred to as autophagy), is the main catabolic mechanism of eukaryotic cells to ensure quality control of the organelles and to maintain nutrient homeostasis. It is regulated by a set of autophagy-related (Atg) proteins involved in doublemembrane vesicles (autophagosomes) formation, maturation and fusion with lysosomes (for a review on autophagy see Ref. [30]). Autophagy can be induced by different stress conditions including nutrient deprivation. One of the key regulators of this process is the mammalian target of rapamycin (mTOR) that inhibits autophagy in the presence of growth factors and nutrients availability. Conversely, the energy sensor AMP-activated protein kinase (AMPK) that responds to AMP accumulation caused by ATP depletion promotes autophagy [31]. Autophagy is involved in various cellular functions and in different pathological and physiological processes. Among these, autophagy has a role in the regulation of stem cells (for review see Ref. [32] and it is required for neurodevelopment and embryonic neurogenesis. In the www.sciencedirect.com
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last years a role of autophagy in adult neurogenesis has also been demonstrated. For example, the pro-autophagic proteins Ambra1 and Beclin1 are highly expressed in the adult mouse SVZ and their downregulation causes a reduction of NSC proliferation and an increase of apoptosis [33]. In the hippocampus autophagy is active in the progeny of the adult NPC and Atg5 is required for their survival, as well as being involved in running-induced hippocampal neurogenesis [34]. Forkhead box O (FoxO) proteins are a highly conserved family of insulin-regulated and growth factor-regulated transcription factors controlling the expression of genes involved in several cell functions, including autophagy. Interestingly, it has been demonstrated that FoxO transcription factors are required to maintain autophagic turnover in adult NSC and NPC and that FoxO-dependent autophagy is necessary for maturation and integration of adult-born hippocampal neurons [35,36]. Moreover, pharmacological induction of autophagy is able to rescue FoxO deficiency-associated morphogenic deficits such as altered dendritic morphology and spine density [35]. The exquisite responsiveness to metabolic and hormonal signals related to the quality/quantity of food intake and the mechanistic link with stem cell function make of autophagy a potential key player in the nutritional modulation of neurogenesis and brain health; however, the relevance of this process in neurogenesis impairment in the context of metabolic disease or vice versa in neurogenic response to calorie restriction or physical exercise, remains to be fully demonstrated.
Gut microbiota, a connection between nutrition and neurogenesis? The gut microbiota, the microorganism community that resides in the gastrointestinal tract, regulates nutrition and metabolism and plays a fundamental role in many host processes including brain development and function [37]. Alterations in the gut microbiota-brain axis have been associated with neurodevelopmental disorders (e.g. autism), stress-related disorders such as depression and anxiety, and cognitive functions [38]. For example, the disruption of colon bacterial community by short-term intragastric treatment of adult mice with antibiotics causes cognitive impairment [39]. Ogbonnaya et al. [40] used germ-free (GF) mice (i.e. animals that have never been exposed to microorganisms) to investigate the involvement of microbiota in neurogenesis. They observed that GF mice have increased neurogenesis in the dorsal hippocampus compared to control (conventionally germ-colonized) mice, and that postweaning microbial colonization has no effect on these differences. They suggest the existence of a ‘window’ period during postnatal development in which microbial colonization can influence adult hippocampal neurogenesis [40]. Nevertheless, the relevance of these yet www.sciencedirect.com
intriguing observations is weakened by the limitations of the GF model, in which several behavioral and brain structure alterations have been reported [41]. In contrast, adult mice subdued to long-term antibiotic treatment so as to deplete gut microbiota, present reduced hippocampal neurogenesis and impaired cognitive function. Probiotic administration or voluntary exercise (running) is able to rescue these antibiotic-induced alterations and also to increase the numbers of Ly6Chi monocytes in the brain. Ly6Chi cells are murine monocytes that infiltrate inflammatory sites and can have context-dependent (beneficial or detrimental) effects in the CNS. 0 Disruption of Ly6Chi monocytes decreases neurogenesis, whereas the transfer of Ly6Chi monocytes rescues neurogenesis after antibiotic treatment, indicating that Ly6Chi monocytes may represent a link between antibiotic-induced alteration of gut microbiota and hippocampal neurogenic response [42]. As mentioned above, many recent studies suggest a strong link between the gut microbiota composition and the development of mental disorders such as depression and anxiety [43]. Along parallel lines of evidence, depression and anxiety have been found associated with an impairment of neurogenesis, while antidepressants stimulate neurogenesis in a fashion that mirrors their clinical efficacy, suggesting the idea that depression could be the result of an altered adult neurogenesis [10], and by extension that microbiota roles in mood disorders may be mechanistically mediated by an impaired neurogenic capacity. Adding to this intriguing view, it was shown already several years ago that antimicrobials-induced alterations of gut microbiota in mice increase exploratory behavior and hippocampal expression of BDNF [44], the latter a neurotrophin pivotal to neuronal growth and survival whose hippocampal levels are also elevated by chronic treatment with different classes of antidepressant drugs. Also of note, the expression of BDNF is increased in different brain regions (i.e. hippocampus, brainstem and hypothalamus) of GF mice [45]. Although in part conflicting, the above evidence clearly outlines a potential gut-brain axis sustained by the resident gut microflora and impacting on hippocampal neurogenesis and by extension on mood disorders. Although the mechanistic details of such circuitry remain to be clarified, BDNF may represent a distal effector, while microbial products, microbe-regulated retinoic acid synthesis [46–48] or microbe-primed inflammatory cells may represent more proximal triggers. Not least, the possibility that microbe effects on adult neurogenesis occur as indirect consequences of an altered systemic inflammatory and metabolic environment remains to be carefully considered [49,50].
Conclusions Unlike in animal model systems, whether adult neurogenesis occurs in humans and significantly contributes to brain function and disease is still a matter of debate [51,52]. Accordingly, very little information is available on the Current Opinion in Pharmacology 2020, 50:46–52
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impact of diet and nutrition/metabolism on postnatal neurogenesis even in its very early stages, and mostly based on (indirect) evidence from in vivo imaging studies on brain structures, or on immune-histochemical analysis of post mortem samples. Relevant to the present article, Page and Xiang reported that exposure to maternal obesity and diabetes during fetal development is associated in children with reduced hippocampal volume and impaired hypothalamic glucose responsiveness predictive of future weight gain [53,54]. Along a different line of investigation, Kafouri et al. found that duration of exclusive breastfeeding (as opposite to infant formula) is an important predictor of parietal cortical thickness (and of general intelligence) in adolescents [55]. However a direct link between these important observations with developmental (or early postnatal) neurogenesis is still missing. Intrauterine exposure to ethanol has devastating effects on brain development in the contest of the Fetal alcoholic spectrum disorder, suggesting that embryonic neurogenesis may represent a relevant target of alcoholic teratogenesis. Interestingly, Druig et al. reported solid immunohistochemical evidence of reduced hippocampal adult neurogenesis in the brain of individuals with a history of alcohol abuse [56]. Besides reflecting a direct toxic effect of ethanol on neural stem cells and progenitors, impaired neurogenesis may result from a compromised general nutritional status as it occurs in alcoholism. In conclusion, the Western lifestyle is increasingly characterized by excessive caloric intake and insufficient physical activity, two factors leading to different metabolic disorders which are a risk factor for cognitive impairment. The evidence that metabolism could play a crucial role in modulating adult neurogenesis, a process involved in brain physiology that helps to ‘keep the brain young’, should be a stimulus for the development of dietary (or pharmacological) interventions to improve neurogenic activity and delay its age-related deterioration.
Conflict of interest statement Nothing declared.
Acknowledgements Virve Cavallucci is supported by the Italian Ministry of Health (Young Researchers Grant GR-2016-02363179). Marco Fidaleo is supported by the Italian Ministry of Health (Young Researchers GR-2016-02364891). Giovambattista Pani is supported by Catholic University Intramural Grants D3.2 2015 and D1 2018. The authors are grateful to Dr. Renata Colavitti for critically reading and commenting the manuscript.
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