Adaptive Synaptogenesis Constructs Neural Codes That Benefit Discrimination

Intelligent organisms face a variety of tasks requiring the acquisition of expertise within a specific domain, including the ability to discriminate between a large number of similar patterns. From an energy-efficiency perspective, effective discrimination requires a prudent allocation of neural resources with more frequent patterns and their variants being represented with greater precision. In this work, we demonstrate a biologically plausible means of constructing a single-layer neural network that adaptively (i.e., without supervision) meets this criterion. Specifically, the adaptive algorithm includes synaptogenesis, synaptic shedding, and bi-directional synaptic weight modification to produce a network with outputs (i.e. neural codes) that represent input patterns proportional to the frequency of related patterns. In addition to pattern frequency, the correlational structure of the input environment also affects allocation of neural resources. The combined synaptic modification mechanisms provide an explanation of neuron allocation in the case of self-taught experts

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

Mortal Computation: A Foundation for Biomimetic Intelligence

This review motivates and synthesizes research efforts in neuroscience-inspired artificial intelligence and biomimetic computing in terms of mortal computation. Specifically, we characterize the notion of mortality by recasting ideas in biophysics, cybernetics, and cognitive science in terms of a theoretical foundation for sentient behavior. We frame the mortal computation thesis through the Markov blanket formalism and the circular causality entailed by inference, learning, and selection. The ensuing framework -- underwritten by the free energy principle -- could prove useful for guiding the construction of unconventional connectionist computational systems, neuromorphic intelligence, and chimeric agents, including sentient organoids, which stand to revolutionize the long-term future of embodied, enactive artificial intelligence and cognition research.Comment: Several revisions applied, corrected error in Jarzynski equality equation (w/ new citaion); references and citations now correctly aligne

REGULATION OF GABAAR SIGNALING AND NEUROADAPTATIONS IN RESPONSE TO DIAZEPAM

Despite 50+ years of use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of GABA, the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABAARs). Sustained treatment with BZD drugs is intimately associated with the development of tolerance, dependence, withdrawal and addiction. BZD efficacy diminishes after prolonged or high dose acute exposure, with tolerance to the sedative/hypnotic effects forming most quickly. We investigated the adaptive mechanisms occurring during initial exposure to the classical BZD, Diazepam (DZP), and the molecular signature of the mouse brain during established sedative tolerance. We found cultured neurons treated 24 h with DZP presented no change in surface or synaptic levels of γ2-GABAARs. In contrast, both γ2 and the key inhibitory synaptic scaffolding protein gephyrin levels were decreased after a single DZP treatment in vitro and in vivo. Live-imaging and label-free quantitative proteomics further revealed alterations in γ2 subunit surface trafficking, internalization and lysosomal targeting. In comparison, mice treated seven days with DZP had altered GABAAR subunit composition, reduced responsiveness to DZP, and tonic inhibition was diminished. Furthermore, DZP increased excitatory NMDA receptor subunit levels and function. State of the art mass spectrometry experiments revealed increased CaMKII subunits, which are positive regulators of NMDA receptors and involved in tolerance to other drugs. Downstream bioinformatics analysis confirmed robust synaptic plasticity after DZP. Together, we describe a time-dependent downregulation of synaptic GABAAR function after initial DZP exposure followed by an adaptive increase in excitatory neurotransmission, neuronal remodeling and altered synaptic GABAAR composition

Alternative polyadenylation as a genetic regulatory mechanism to bridge genome to phenome in the context of appetitive behaviors.

Energy is essential for life. On one end of the spectrum, over 1/3 of Americans live with obesity, which only occurs when excess energy is consumed and stored by the body. Obesity is comorbid with Type II diabetes, heart disease, and cancer, and is estimated to cost $147 billion United State dollars annually in economic expenditures. On the other end of the spectrum, more than 1/3 of cancer patients die from body wasting, not the cancer itself. One pertinent feature that contributes to body wasting is anorexia, or the loss of appetite. Even though the neuronal networks responsible for the control of energy balance and appetite are understood, how these networks are functionally adapted to environmental circumstances to maintain energy homeostasis is not yet well investigated. In this context, alternative polyadenylation is a post-transcriptional RNA processing mechanism that may functionally mediate environment x gene interactions. Over 70% of human transcripts undergo alternative polyadenylation, a process by which the selective use of canonical AAUAAA polyadenylation sites generate transcriptional diversity. The alternative use of polyadenylation sites is an important regulatory mechanism that establishes transcript maturation, stability, and localization, all of which are key aspects of gene expression in neuronal cells to coordinate behavioral responses.This dissertation explores alternative polyadenylation in relation to appetite. The presented data indicate that 1) sex differences occur in a model of binge-like feedings in rats, 2) alternative polyadenylation is a post-transcriptional processing mechanism that is impacted by either diet-induced obesity or cannabis exposure in the brain’s endogenous appetite center, the hypothalamus, and 3) the alternative polyadenylation site on the 3′ untranslated region of the Timp2 transcript, identified as having distal alternative polyadenylation site use upregulation in diet-induced obesity, functionally mediates spinogenesis in hippocampal primary neurons. Collectively, this work contributes to a more comprehensive understanding of the neurobiological controls of appetite and elucidates alternative polyadenylation as a key post-transcriptional processing mechanism that modulates in response to appetitive state

Molecular Mechanisms of Pre- and Postsynaptic Ephb/ephrin-B Signaling in Synapse Formation and Function

Proper function of the central nervous system relies on precise and coordinated cell-cell interactions and communication via synaptic transmission to assemble neuronal networks. Aberrant synaptic transmission is a hallmark of neuronal disease. The EphB family of receptor tyrosine kinases and their ephrin-B ligands play critical roles in the central nervous system in axon guidance, formation of pre- and post-synaptic specializations, localization of glutamate receptors, synaptic plasticity, and disease. EphB/ephrin-B signaling has been reported to modulate these processes, but the molecular mechanisms remain poorly understood. Our laboratory has previously shown that EphBs organize the formation of both pre- and postsynaptic specializations, and interact directly with NMDA-type glutamate receptors. Therefore, I sought to investigate the molecular mechanisms for formation of presynaptic specializations and the interaction domain between EphBs and NMDA receptors. I found that EphBs can induce the formation of presynaptic specializations by trans-synaptic interactions with both ephrin-B1 and ephrin-B2. These ephrin-Bs can then recruit the machinery for neurotransmitter release through the multiple PDZ-domain containing adaptor protein syntenin-1. Furthermore, ephrin-B1 and ephrin-B2 act independently for formation of presynaptic specializations, but together to recruit syntenin-1 to synaptic sites. Based on this work and that of other laboratories, I was able to define the molecular pathway from postsynaptic EphBs to presynaptic glutamatergic vesicles. Furthermore, on the postsynaptic side of the synapse, I define a single amino acid that is necessary and sufficient to mediate the EphB-NMDAR interaction. In a novel molecular mechanism, I show that extracellular phosphorylation of this residue after ephrin-B binding is sufficient to induce the EphB-NMDAR interaction. Furthermore, I show that in the mature brain, the EphB-NMDAR interaction preferentially regulates NR2B-subunit containing NMDA receptor localization, function, and downstream gene transcription. Together, these findings impact our understanding of synapse formation and function, and highlight the EphB-NMDAR interaction as a potential target to treat neurological disease

Coordinate and Region-Specific Roles for Fibroblast Growth Factors 2 and 9 as Molecular Organizers in Major Depression and Animal Models of Affective Disorders.

The neurotrophic hypothesis posits that changes in the expression and function of growth factors in the brain underlie the pathophysiology of Major Depressive Disorder (MDD). Previous work implicated the fibroblast growth factor (FGF) system, identifying FGF2 as an endogenous anxiolytic and antidepressant molecule whose expression is downregulated in the depressed brain. Notably, FGF9 showed a diagnosis-specific pattern of expression that was opposite to FGF2. Therefore, we investigated the hypotheses that FGF2 and FGF9 were critical to the regulation of affect and that their expression becomes disrupted in MDD. Because the literature supporting the role of FGF9 in affect regulation was small, we performed exploratory analyses and demonstrated that FGF9 expression is consistently upregulated in the hippocampus (but not the anterior cingulate cortex or dorsolateral prefrontal cortex) of individuals diagnosed with MDD. We also showed that reducing endogenous expression of FGF9 in the dentate gyrus is sufficient to reduce anxiety-like behavior, and hippocampal FGF9 levels differ in an animal model of affective dysregulation. Because they showed opposite effects in MDD and animal models, we hypothesized that FGF2 and FGF9 might act as physiological antagonists to mediate affect. We examined more complex questions regarding FGF2. We used animal models to demonstrate that altered hippocampal FGF2 expression predisposes individuals for affective dysregulation. Because we hypothesized that relative levels of FGF2 and FGF9 might be important to MDD pathophysiology, we examined diagnosis-specific relationships in expression between FGF2, FGF9, and FGF receptors, and we found regional patterns of alteration with MDD. In the anterior cingulate cortex, correlations between FGF family members were lost in MDD, while in the hippocampus, new relationships emerged. These changes were related to alterations in correlated gene expression of transcripts related to fundamental biology and circuit function, supporting the hypothesis that FGF2 and FGF9 may influence affect by acting as molecular organizers whose effects become dysregulated during MDD. Future studies will examine the role of FGF2 and FGF9 in MDD, with a particular emphasis on understanding how neural circuitry is altered at the cellular level.PhDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/133376/1/eaurbach_1.pd

Mitochondrial trafficking in healthy and injured neurons

Mitochondria are the primary generators of ATP and are important regulators of intracellular calcium homeostasis. These organelles are dynamically transported along lengthy neuronal processes, presumably for appropriate distribution to cellular regions of increased need such as synapses. The removal of damaged mitochondria that produce harmful reactive oxygen species and promote apoptosis is also thought to be mediated by mitochondrial transport to autophagosomes. Mitochondrial trafficking is therefore important for maintaining neuronal and mitochondrial health while cessation of movement may lead to neuronal and mitochondrial dysfunctions.The demands for mitochondria differ between developing and mature neurons, and separate mitochondrial recruitment signals have been identified in each case. In the first aim, we examined how mitochondrial dynamics are affected by the development of synaptic connections in cortical neurons. We revealed reduced mitochondrial movement and elongated morphology in mature neurons which probably serve to optimize mitochondrial contact with synaptic sites.Synapses require mitochondria to supply ATP and regulate local [Ca2+]i for neurotransmission. The second aim investigated mitochondrial trafficking patterns relative to synaptic sites on axons and dendrites. We demonstrated that synapses are targets for long-term mitochondrial localization and dynamic recruitment of moving mitochondria, and that trafficking patterns are influenced by changes in synaptic activity. We also found that mitochondrial movement in dendrites is more severely impaired by neurotoxic glutamate and zinc exposures than in axons. These findings suggest a mechanism for postsynaptic dysfunction and dendritic degeneration in excitotoxicity.The third aim examined impaired mitochondrial transport as an early pathogenic mechanism in Huntington's disease. Recent studies indicate that aggregates composed of mutant huntingtin fragments hinder axonal transport by sequestering wildtype huntingtin, cytoskeletal components and molecular motors. Our studies in cortical neurons demonstrated reduced mitochondrial trafficking specifically to sites of aggregates and impeded passage of moving mitochondria by aggregates resulting in discrete regions of mitochondrial accumulation and immobilization.In summary, this dissertation provides new insight into our understanding of mitochondrial trafficking, morphology and distribution in cortical neurons that are developing, synaptically mature, acutely injured, and diseased. We conclude that mitochondrial movement is dynamic in healthy neurons and that injured neurons exhibit different manifestations of impaired movement