Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.	After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.
2.	The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).
3.	The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 
4.	This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 
5.	Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 
6.	Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.
7.	Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 
8.	Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. 
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Human metabolic adaptations and prolonged expensive neurodevelopment: A review

1.	After weaning, human hunter-gatherer juveniles receive substantial (≈3.5-7 MJ day^-1^), extended (≈15 years) and reliable (kin and nonkin food pooling) energy provision.
2.	The childhood (pediatric) and the adult human brain takes a very high share of both basal metabolic rate (BMR) (child: 50-70%; adult: ≈20%) and total energy expenditure (TEE) (child: 30-50%; adult: ≈10%).
3.	The pediatric brain for an extended period (≈4-9 years-of-age) consumes roughly 50% more energy than the adult one, and after this, continues during adolescence, at a high but declining rate. Within the brain, childhood cerebral gray matter has an even higher 1.9 to 2.2-fold increased energy consumption. 
4.	This metabolic expensiveness is due to (i) the high cost of synapse activation (74% of brain energy expenditure in humans), combined with (ii), a prolonged period of exuberance in synapse numbers (up to double the number present in adults). Cognitive development during this period associates with volumetric changes in gray matter (expansion and contraction due to metabolic related size alterations in glial cells and capillary vascularization), and in white matter (expansion due to myelination). 
5.	Amongst mammals, anatomically modern humans show an unique pattern in which very slow musculoskeletal body growth is followed by a marked adolescent size/stature spurt. This pattern of growth contrasts with nonhuman primates that have a sustained fast juvenile growth with only a minor period of puberty acceleration. The existence of slow childhood growth in humans has been shown to date back to 160,000 BP. 
6.	Human children physiologically have a limited capacity to protect the brain from plasma glucose fluctuations and other metabolic disruptions. These can arise in adults, during prolonged strenuous exercise when skeletal muscle depletes plasma glucose, and produces other metabolic disruptions upon the brain (hypoxia, hyperthermia, dehydration and hyperammonemia). These are proportional to muscle mass.
7.	Children show specific adaptations to minimize such metabolic disturbances. (i) Due to slow body growth and resulting small body size, they have limited skeletal muscle mass. (ii) They show other adaptations such as an exercise specific preference for free fatty acid metabolism. (iii) While children are generally more active than adolescents and adults, they avoid physically prolonged intense exertion. 
8.	Childhood has a close relationship to high levels of energy provision and metabolic adaptations that support prolonged synaptic neurodevelopment. 
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Mechanisms Mediating Adaptive Presynaptic Muting Induction

Neurons are responsible for information processing within the nervous system, so strong perturbations of neuronal function have far-reaching consequences within the neural network. Damage in response to excess excitation, as occurs during stroke or seizure, is known as excitotoxicity. One method utilized by neurons for reducing excitotoxicity within an overly activated neuronal network is to arrest excitatory neurotransmitter release from presynaptic terminals. The mechanisms responsible for inducing this presynaptic silencing: or muting ), however, have been elusive. In order to elucidate the signals responsible, I used molecular techniques in defined networks of cultured neurons from the mammalian hippocampus, a well-studied brain region known to be important for learning and memory but susceptible to excitotoxic damage. Calcium serves as a signal transducer during excitotoxicity and many forms of synaptic plasticity, but the signaling cascades in presynaptic silencing were previously unknown. In neurons individually depolarized via heterologous ion channel activation, I showed that calcium influx led to cell death while channel expression led to synaptic depression, although muting was not confirmed. Calcium, however, was not necessary for presynaptic muting after strong depolarization. Instead, inhibitory G-protein signaling induced silencing through cyclic adenosine monophosphate: cAMP) reduction but surprisingly not via activation of likely candidate receptors. This cAMP reduction contributed to loss of proteins important for vesicle fusion at the presynaptic terminal. I also found that astrocytes, support cells in the nervous system that have garnered attention recently for their ability to modulate neuronal function, were required for the proper development of presynaptic muting in hippocampal neurons. Soluble factors released by astrocytes were permissive, but not instructive, for silencing induction. Thrombospondins were identified as the astrocyte-derived factors responsible for muting competence in neurons, and they act through binding to the a2d-1 subunit of voltage-gated calcium channels. cAMP-activated protein kinase A exhibited dysfunctional behavior in the absence of thrombospondins, potentially explaining the presynaptic muting deficit in an astrocyte-deficient environment. Together these results clarify the molecular mechanisms responsible for an underappreciated form of neuroprotective synaptic plasticity and provide potential therapeutic targets for a number of disorders expressing excitotoxic damage

As aplicações de TLBL podem melhorar os aspectos do TEA relacionados a distúrbios no microbioma intestinal, atividade mitocondrial e função da rede neural

Autism Spectrum Disorder constitutes a complex, elaborate, and diverse condition at a developmental, biological, and neurophysiological level. It is recognized primarily by the behavioral manifestations of the individual in communication, social interaction, and by extension in his cognitive development and adaptation to society as a whole. A wide range of studies have linked the pathophysiology of autism to dysfunctional elements in the development and function of mitochondria, cells, neurons, and the gastrointestinal microbiome. Low Light Laser Therapy (LLLT) is an innovative, emerging, non-invasive treatment method. It utilizes low levels of red light/near-infrared light positively affecting biological and pathological processes of the body by enhancing cellular, mitochondrial stimulation, neurogenesis, synaptogenesis, and immune system development, regulating the gut microbiome's function. The retrospective literature review focuses on the possibility of effective use of the method in autism. According to the literature, LLLT does not have many applications in patients with ASD and is still in the early stages of its use in the disorder. However, the results of the studies highlight its therapeutic effect in several areas related to the disease, pointing out that it is a promising therapeutic approach for the evolution of autism in the future.El Trastorno del Espectro Autista constituye una condición compleja, elaborada y diversa a nivel del desarrollo, biológico y neurofisiológico. Se reconoce principalmente por las manifestaciones conductuales del individuo en la comunicación, la interacción social y por extensión en su desarrollo cognitivo y adaptación a la sociedad en su conjunto. Una amplia gama de estudios ha relacionado la fisiopatología del autismo con elementos disfuncionales en el desarrollo y función de las mitocondrias, las células, las neuronas y el microbioma gastrointestinal. La terapia con láser con poca luz (LLLT) es un método de tratamiento innovador, emergente y no invasivo. Utiliza niveles bajos de luz roja/luz infrarroja cercana que afectan positivamente los procesos biológicos y patológicos del cuerpo al mejorar la estimulación celular, mitocondrial, la neurogénesis, la sinaptogénesis y el desarrollo del sistema inmunológico, regulando la función del microbioma intestinal. La revisión retrospectiva de la literatura se centra en la posibilidad de un uso eficaz del método en el autismo. Según la literatura, la LLLT no tiene muchas aplicaciones en pacientes con TEA y aún se encuentra en las primeras etapas de su uso en el trastorno. Sin embargo, los resultados de los estudios destacan su efecto terapéutico en varias áreas relacionadas con la enfermedad, señalando que es un enfoque terapéutico prometedor para la evolución del autismo en el futuro.O Transtorno do Espectro Autista constitui uma condição complexa, elaborada e diversificada em nível de desenvolvimento, biológico e neurofisiológico. É reconhecida principalmente pelas manifestações comportamentais do indivíduo na comunicação, interação social e, por extensão, em seu desenvolvimento cognitivo e adaptação à sociedade como um todo. Uma ampla gama de estudos ligou a fisiopatologia do autismo a elementos disfuncionais no desenvolvimento e função das mitocôndrias, células, neurônios e do microbioma gastrointestinal. Terapia a laser de baixa luminosidade (TLBL) é um método de tratamento inovador, emergente e não invasivo. Ele utiliza baixos níveis de luz vermelha/luz quase infravermelha (NIR) afetando positivamente os processos biológicos e patológicos do corpo, melhorando a estimulação celular, mitocondrial, neurogênese, sinaptogênese e desenvolvimento do sistema imunológico, regulando a função do microbioma intestinal. A revisão retrospectiva da literatura enfoca a possibilidade de uso efetivo do método no autismo. De acordo com a literatura, a TLBL não tem muitas aplicações em pacientes com TEA e ainda está em estágios iniciais de seu uso no transtorno. No entanto, os resultados dos estudos destacam seu efeito terapêutico em diversas áreas relacionadas à doença, apontando que é uma abordagem terapêutica promissora para a evolução do autismo no futuro

Metabolic Changes Following Perinatal Asphyxia: Role of Astrocytes and Their Interaction with Neurons

Perinatal Asphyxia (PA) represents an important cause of severe neurological deficits including delayed mental and motor development, epilepsy, major cognitive deficits and blindness. The interaction between neurons, astrocytes and endothelial cells plays a central role coupling energy supply with changes in neuronal activity. Traditionally, experimental research focused on neurons, whereas astrocytes have been more related to the damage mechanisms of PA. Astrocytes carry out a number of functions that are critical to normal nervous system function, including uptake of neurotransmitters, regulation of pH and ion concentrations, and metabolic support for neurons. In this work, we aim to review metabolic neuron-astrocyte interactions with the purpose of encourage further research in this area in the context of PA, which is highly complex and its mechanisms and pathways have not been fully elucidated to this day.Fil: Logica Tornatore, Tamara Maite Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Riviere, Stephanie. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Holubiec, Mariana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Castilla Lozano, Maria del Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Barreto, George E.. Pontificia Universidad Javeriana; ColombiaFil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina. Universidad Argentina "John F. Kennedy"; Argentina. Universidad Autónoma de Chile; Chil

Applications of Biological Cell Models in Robotics

In this paper I present some of the most representative biological models applied to robotics. In particular, this work represents a survey of some models inspired, or making use of concepts, by gene regulatory networks (GRNs): these networks describe the complex interactions that affect gene expression and, consequently, cell behaviour

Neuroplasticity to autophagy cross-talk in a therapeutic effect of physical exercises and irisin in ADHD

Adaptive neuroplasticity is a pivotal mechanism for healthy brain development and maintenance, as well as its restoration in disease- and age-associated decline. Management of mental disorders such as attention deficit hyperactivity disorder (ADHD) needs interventions stimulating adaptive neuroplasticity, beyond conventional psychopharmacological treatments. Physical exercises are proposed for the management of ADHD, and also depression and aging because of evoked brain neuroplasticity. Recent progress in understanding the mechanisms of muscle-brain cross-talk pinpoints the role of the myokine irisin in the mediation of pro-cognitive and antidepressant activity of physical exercises. In this review, we discuss how irisin, which is released in the periphery as well as derived from brain cells, may interact with the mechanisms of cellular autophagy to provide protein recycling and regulation of brain-derived neurotrophic factor (BDNF) signaling via glia-mediated control of BDNF maturation, and, therefore, support neuroplasticity. We propose that the neuroplasticity associated with physical exercises is mediated in part by irisin-triggered autophagy. Since the recent findings give objectives to consider autophagy-stimulating intervention as a prerequisite for successful therapy of psychiatric disorders, irisin appears as a prototypic molecule that can activate autophagy with therapeutic goals

Mitochondrial Regulators of Synaptic Plasticity in the Ischemic Brain

Synaptic plasticity is a process by which neurons adapt or alter the strength of information transfer, and it is known to play a role in memory formation, learning, and recovery after injury. In this chapter, we describe how ischemic insults alter neuronal intracellular mechanisms and signaling pathways, and we discuss how, after neuronal injury, synaptic plasticity is regulated prior to and during death or rehabilitation and recovery. In addition, recently described regulators of synaptic plasticity will be introduced

TrkB- ja ERK-signalointi NMDA-reseptoria salpaavien masennuslääkkeiden mekanismissa

Subanesteettinen annos ketamiinia, N-metyyli-D-aspartaatti (NMDA)-reseptorin salpaajaa, lievittää masennuksen oireita nopeasti, ja vaikutus kestää kauan sen elimistöstä poistumisen jälkeen. Vaikka tarkka mekanismi ei ole vielä selvillä, on TrkB (tropomyosiinireseptorikinaasi B), ERK (solunulkoisen signaalin säätelemä kinaasi 1 ja 2), GSK3β (glykogeenisyntaasikinaasi 3β) ja mTOR (engl. mammalian target of rapamycin)-signaloinnin säätely etuaivokuorella yhdistetty ketamiinin masennuslääkkeenkaltaisiin vaikutuksiin jyrsijöillä. Lisäksi α-amino-3-hydroksi-5-metyyli-4-isoksatsolipropionihappo (AMPA)-reseptorien aktivaation ajatellaan olevan tärkeä osa sen mekanismia. Typpioksiduuli (N2O), joka niin ikään on NMDA-reseptorin antagonisti ja otaksuttu nopeavaikutteinen masennuslääke, säätelee samoja molekulaarisia signalointireittejä jyrsijöiden etuaivokuorella kuin ketamiini. Typpioksiduulin nopeaa farmakokinetiikkaa hyödyntämällä on huomattu, että sen akuuttien farmakologisten vaikutusten (NMDA-reseptorin salpauksen) aikana havaitaan lisääntynyt ERK:n fosforylaatio ja muita hermosolujen eksitaatioon liitettyjä signalointimuutoksia, kun taas TrkB:n, GSK3β:n ja P70S6K:n fosforylaation säätely ilmenee vasta typpioksiduulin eliminaation jälkeen. Tämän tutkimuksen ensimmäisessä osassa tutkimme typpioksiduulin aiheuttamia hermosolujen eksitaatioon ja BDNF-TrkB signalointiin liittyviä biokemiallisia muutoksia etuaivokuorella, ja lisäksi, AMPA-reseptorien aktivaation roolia näiden aikaansaamisessa. Keskityimme muutoksiin, jotka nähdään typpioksiduulin akuuttien farmakologisten vaikutusten jälkeen. Aikuisille C57BL/6-linjan uroshiirille annosteltiin 65% typpioksiduulia 20 minuutin ajan sen jälkeen, kun ne olivat saaneet injektiona joko AMPA-reseptorin salpaajaa (NBQX, 10 mg/kg) tai kontrolliliuosta (fysiologista suolaliuosta). Etuaivokuoren näytteet kerättiin 15 minuuttia typpioksiduulin annon lopettamisen jälkeen, jolloin sen oletetaan eliminoituneen elimistöstä kokonaan. Näytteet analysoitiin käyttäen western blot, ELISA (engl. enzyme-linked immunosorbent assay) ja RT-qPCR (kvantitatiivinen käänteistranskriptaasi PCR) menetelmiä. Havaitsimme, että typpioksiduuli lisäsi TrkB:n, GSK3β:n ja P70S6K:n fosforylaatiotasoja riippumatta siitä, olivatko eläimet saaneet ennen typpioksiduulia NBQX- vai suolaliuos-injektion. Samanaikaisesti ERK:n fosforylaatiossa nähtiin typpioksiduulin annon jälkeen väheneminen, joka oli heikentynyt eläimillä, jotka saivat NBQX:ää ennen typpioksiduulia. BDNF-proteiinin tai sen lähetti-RNA:n (eksoni IV) kudostasoissa ei havaittu muutoksia ryhmien välillä. Tulokset viittaavat siihen, että typpioksiduulin aikaansaama TrkB:n ja ERK:n säätely on toisistaan riippumatonta. AMPA-reseptorin aktivaatio ei näytä vaikuttavan TrkB-signalointiin, vaikka se saattaa säädellä ERK-signalointia. Lisäksi TrkB:n lisääntynyt fosforylaatio typpioksiduulin annon jälkeen tapahtuu ilman, että BDNF:n kudostasot nousevat. Tutkimuksen toisessa osassa tavoitteena oli etsiä ketamiininkaltaisia NMDA-reseptorin salpaajia, joilla on potentiaalisia masennuslääkevaikutuksia. Löytääksemme kaupallisia ketamiinianalogeja, suoritimme tietokoneavusteisesti osarakennehaun ketamiinin rakenteeseen perustuen. Löydetyt ketamiinianalogit suodatettiin niiden laskennallisten ADMET-ominaisuuksien perusteella, jonka jälkeen suoritettiin virtuaalinen seulonta telakoimalla yhdisteet NMDA-reseptorikompleksiin (protein data bank-koodi: 4TLM) ionikanavan alueelle, ketamiinin ennustetun sitoutumispaikan läheisyyteen. Lopuksi pyrimme selvittämään, saavatko valitut ketamiinianalogit aikaan ketamiininkaltaisia vaikutuksia TrkB- ja ERK- signalointiin primaarisessa hermosoluviljelmässä. Emme kuitenkaan edenneet testaamaan ketamiinianalogeja, sillä ketamiini (positiivinen kontrolli) ei vaikuttanut TrkB:n tai ERK:n fosforylaatioon meidän viljelmässämme. Kaiken kaikkiaan tämä tutkimus edistää ymmärrystä typpioksiduulin mekanismista, joka mahdollisesti valottaa myös yleisemmin NMDA-reseptoria salpaavien masennuslääkkeiden mekanismia. Lisäksi löysimme lupaavia ketamiinianalogeja, jotka odottavat kokeellista testausta.Subanesthetic-dose ketamine, an N-methyl-D-aspartate receptor (NMDAR) blocker, exerts rapid antidepressant effects that sustain long after its elimination from the body. The precise mechanism remains unknown, but regulation of TrkB (tropomyosin receptor kinase B), ERK (extracellular-regulated kinase 1 and 2), GSK3β (glycogen synthase kinase 3β) and mTOR (mammalian target of rapamycin) signaling within the prefrontal cortex (PFC) have been deemed important for its antidepressant-like effects in rodents. In addition, activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is thought to be an important step in its mechanism. Nitrous oxide (N2O), another NMDAR antagonist and a putative rapid-acting antidepressant, regulates the same molecular pathways as ketamine in the rodent PFC. The fast pharmacokinetics of N2O have been exploited to show that markers of neuronal excitation, including phosphorylation of ERK, are upregulated in the PFC during its acute pharmacological effects (NMDAR blockade), while regulation of TrkB, GSK3β and P70S6K emerges only upon N2O withdrawal. In the first part of this study, we investigated the N2O-induced biochemical changes associated with neuronal excitation and BDNF-TrkB signaling in the PFC and further, the requirement for AMPAR activation in inducing them. We focused on the effects seen after the acute pharmacological effects of N2O. N2O (65% for 20 min) was administered to adult male C57BL/6 mice with or without pretreatment with AMPAR antagonist (NBQX, 10 mg/kg) and PFC samples were collected 15 minutes after stopping N2O delivery. Within this time N2O is expected to be completely eliminated. The brain samples were analyzed using western blot, enzyme-linked immunosorbent assay and quantitative reverse transcription PCR. We observed that N2O increased levels of phosphorylated TrkB, GSK3β and P70S6K, and these effects were not attenuated by NBQX pretreatment. At the same time, we observed a decrease in the levels of phosphorylated ERK, which was attenuated in mice that received NBQX prior to N2O. Tissue levels of BDNF protein or messenger RNA (exon IV) were not different between control and experimental groups. These results indicate that the mechanism of N2O is associated with TrkB and ERK signaling that are regulated independently of each other. It appears that AMPAR activation is not required for TrkB signaling, although it might play a role in ERK signaling. Further, N2O-induced TrkB phosphorylation in the PFC is not associated with changes in total levels of BDNF. In the second part of the study, we aimed to search for new ketamine-like NMDAR blockers with antidepressant potential. Ketamine was used as a query compound for in silico substructure search to find commercial ketamine analogs. The retrieved ketamine analogs were filtered by their computed ADMET properties and then further screened virtually by docking them to the pore region of NMDAR complex (protein data bank code: 4TLM), around the predicted binding site of ketamine. Finally, we sought to study if selected ketamine analogs could elicit ketamine-like effects on TrkB and ERK signaling in mouse primary cortical neurons. However, we did not proceed to test the analogs since ketamine (positive control) did not show any effects on TrkB or ERK phosphorylation in our culture. Overall, this study advances the understanding of the mechanism of N2O, possibly giving new insight of the antidepressant mechanisms of NMDAR-blocking agents more generally. Additionally, we found promising ketamine analogs that await experimental testing