[Treatment of diseases with consequences of traumatic brain injury]. / Lechenie bol'nykh s posledstviyami cherepno-mozgovoi travmy.

Traumatic brain injury (TBI) is one of the leading causes of neurological morbidity, disability and mortality in all age groups of the population. As a result of the general increase in the number of cases of brain injuries, there is a significant increase in the consequences of TBI, the dominant part of which is asthenic, vegetative, cognitive, emotional and liquorodynamic disorders. Therapeutic measures in the long-term period of TBI should be carried out intensively as in the first 12 months. after TBI, and in the future, considering the ongoing processes of morphofunctional maturation of the CNS and high brain plasticity, especially in childhood. Syndromic treatment should be differentiated and pathogenetically substantiated. The article covers in detail the modern methods of drug therapy in patients with remote residual effects of brain injury. The high efficiency of the use of the neuroprotective drug Cortexin in the correction of the consequences of TBI was shown.

Evolution of neural activity in circuits bridging sensory and abstract knowledge.

The ability to associate sensory stimuli with abstract classes is critical for survival. How are these associations implemented in brain circuits? And what governs how neural activity evolves during abstract knowledge acquisition? To investigate these questions, we consider a circuit model that learns to map sensory input to abstract classes via gradient-descent synaptic plasticity. We focus on typical neuroscience tasks (simple, and context-dependent, categorization), and study how both synaptic connectivity and neural activity evolve during learning. To make contact with the current generation of experiments, we analyze activity via standard measures such as selectivity, correlations, and tuning symmetry. We find that the model is able to recapitulate experimental observations, including seemingly disparate ones. We determine how, in the model, the behaviour of these measures depends on details of the circuit and the task. These dependencies make experimentally testable predictions about the circuitry supporting abstract knowledge acquisition in the brain.

Learning predictive cognitive maps with spiking neurons during behavior and replays.

The hippocampus has been proposed to encode environments using a representation that contains predictive information about likely future states, called the successor representation. However, it is not clear how such a representation could be learned in the hippocampal circuit. Here, we propose a plasticity rule that can learn this predictive map of the environment using a spiking neural network. We connect this biologically plausible plasticity rule to reinforcement learning, mathematically and numerically showing that it implements the TD-lambda algorithm. By spanning these different levels, we show how our framework naturally encompasses behavioral activity and replays, smoothly moving from rate to temporal coding, and allows learning over behavioral timescales with a plasticity rule acting on a timescale of milliseconds. We discuss how biological parameters such as dwelling times at states, neuronal firing rates and neuromodulation relate to the delay discounting parameter of the TD algorithm, and how they influence the learned representation. We also find that, in agreement with psychological studies and contrary to reinforcement learning theory, the discount factor decreases hyperbolically with time. Finally, our framework suggests a role for replays, in both aiding learning in novel environments and finding shortcut trajectories that were not experienced during behavior, in agreement with experimental data.

Dietary choline metabolite TMAO impairs cognitive function and induces hippocampal synaptic plasticity declining through the mTOR/P70S6K/4EBP1 pathway.

Mild cognitive impairment (MCI) is an intermediate state between "healthy" and "dementia", which affects memory and cognitive function. Timely intervention and treatment of MCI can effectively prevent it from developing into an incurable neurodegenerative disease. Lifestyle factors, such as dietary habits, were highlighted as risk factors for MCI. The effect of a high-choline diet on cognitive function is contentious. In this study, we focus our attention on the choline metabolite trimethylamine-oxide (TMAO), an acknowledged pathogenic molecule of cardiovascular disease (CVD). With recent studies indicating that TMAO also plays a potential role in the central nervous system (CNS), we aim to explore the effect of TMAO on synaptic plasticity in the hippocampus, the basic structure of studying and memory. Using various hippocampal-dependent spatial references or working memory-related behavioral texts, we found that TMAO treatment caused both long-term memory (LTM) and short-term memory (STM) deficits in vivo. Simultaneously, the plasm and whole brain levels of choline and TMAO were measured by employing liquid phase mass spectrometry (LC/MS). Furthermore, the effects of TMAO on the hippocampus were further explored by applying Nissl staining and transmission electron microscopy (TEM). Moreover, the expression of synaptic plasticity-related proteins, including synaptophysin (SYN), postsynaptic density protein95 (PSD95), and N-methyl-aspartate receptor (NMDAR), was examined by western blotting and immunohistochemical (IHC). The results showed that TMAO treatment contributes to neuron loss, synapse ultrastructure alteration, and synaptic plasticity impairments. In mechanism, the mammalian target of rapamycin (mTOR) regulates synaptic function, and the activation of the mTOR signaling pathway was observed in TMAO groups. In conclusion, this study confirmed that the choline metabolite TMAO can induce hippocampal-dependent learning and memory ability impairment with synaptic plasticity deficits by activating the mTOR signaling pathway. The effects of choline metabolites on cognitive function may provide a theoretical basis for establishing the daily reference intakes (DRIs) of choline.

Mir125b-2 imprinted in human but not mouse brain regulates hippocampal function and circuit in mice.

Genomic imprinting predominantly occurs in the placenta and brain. Few imprinted microRNAs have been identified in the brain, and their functional roles in the brain are not clear. Here we show paternal, but not maternal, expression of MIR125B2 in human but not mouse brain. Moreover, Mir125b-2m-/p- mice showed impaired learning and memory, and anxiety, whose functions were hippocampus-dependent. Hippocampal granule cells from Mir125b-2m-/p- mice displayed increased neuronal excitability, increased excitatory synaptic transmission, and decreased inhibitory synaptic transmission. Glutamate ionotropic receptor NMDA type subunit 2A (Grin2a), a key regulator of synaptic plasticity, was physically bound by miR-125b-2 and upregulated in the hippocampus of Mir125b-2m-/p- mice. Taken together, our findings demonstrate MIR125B2 imprinted in human but not mouse brain, mediated learning, memory, and anxiety, regulated excitability and synaptic transmission in hippocampal granule cells, and affected hippocampal expression of Grin2a. Our work provides functional mechanisms of a species-specific imprinted microRNA in the brain.

Sex differences and hormonal regulation of metabotropic glutamate receptor synaptic plasticity.

Striking sex differences exist in presentation and incidence of several psychiatric disorders. For example, major depressive disorder is more prevalent in women than men, and women who develop alcohol use disorder progress through drinking milestones more rapidly than men. With regards to psychiatric treatment responses, women respond more favorably to selective serotonin reuptake inhibitors than men, whereas men have better outcomes when prescribed tricyclic antidepressants. Despite such well-documented biases in incidence, presentation, and treatment response, sex as a biological variable has long been neglected in preclinical and clinical research. An emerging family of druggable targets for psychiatric diseases, metabotropic glutamate (mGlu) receptors are G-protein coupled receptors broadly distributed throughout the central nervous system. mGlu receptors confer diverse neuromodulatory actions of glutamate at the levels of synaptic plasticity, neuronal excitability, and gene transcription. In this chapter, we summarize the current preclinical and clinical evidence for sex differences in mGlu receptor function. We first highlight basal sex differences in mGlu receptor expression and function and proceed to describe how gonadal hormones, notably estradiol, regulate mGlu receptor signaling. We then describe sex-specific mechanisms by which mGlu receptors differentially modulate synaptic plasticity and behavior in basal states and models relevant for disease. Finally, we discuss human research findings and highlight areas in need of further research. Taken together, this review emphasizes how mGlu receptor function and expression can differ across sex. Gaining a more complete understanding of how sex differences in mGlu receptor function contribute to psychiatric diseases will be critical in the development of novel therapeutics that are effective in all individuals.

Dynamic effects of bilingualism on brain structure map onto general principles of experience-based neuroplasticity.

Bilingualism has been linked to structural adaptations of subcortical brain regions that are important for controlling multiple languages. However, research on the location and extent of these adaptations has yielded variable patterns, especially as far as the subcortical regions are concerned. Existing literature on bilingualism-induced brain restructuring has so far largely overseen evidence from other domains showing that experience-based structural neuroplasticity often triggers non-linear adaptations which follow expansion-renormalisation trajectories. Here we use generalised additive mixed models to investigate the non-linear effects of quantified bilingual experiences on the basal ganglia and the thalamus in a sample of bilinguals with a wide range of bilingual experiences. Our results revealed that volumes of the bilateral caudate nucleus and nucleus accumbens were significantly related to bilingual experiences. Importantly, these followed a non-linear pattern, with increases followed by plateauing in the most experienced bilinguals, suggesting that experience-based volumetric increases are only necessary up to a certain level of bilingual experience. Moreover, the volumes of putamen and thalamus were positively predicted by bilingual experiences. The results offer the first direct evidence that bilingualism, similarly to other cognitively demanding skills, leads to dynamic subcortical structural adaptations which can be nonlinear, in line with expansion-renormalisation models of experience-dependent neuroplasticity.

Berberine ameliorates depression-like behaviors in mice via inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing neuroplasticity disruption.

OBJECTIVES: Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. METHODS: Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi-Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. RESULTS: The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. CONCLUSION: The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.

Analysis of Axonal Regrowth and Dendritic Remodeling After Optic Nerve Crush in Adult Zebrafish.

Neurodegenerative diseases and central nervous system (CNS) injuries are frequently characterized by axonal damage, as well as dendritic pathology. In contrast to mammals, adult zebrafish show a robust regeneration capacity after CNS injury and form the ideal model organism to further unravel the underlying mechanisms for both axonal and dendritic regrowth upon CNS damage. Here, we first describe an optic nerve crush injury model in adult zebrafish, an injury paradigm that inflicts de- and regeneration of the axons of retinal ganglion cells (RGCs), but also triggers RGC dendrite disintegration and subsequent recovery in a stereotyped and timed process. Next, we outline protocols for quantifying axonal regeneration and synaptic recovery in the brain, using retro- and anterograde tracing experiments and an immunofluorescent staining for presynaptic compartments, respectively. Finally, methods to analyze RGC dendrite retraction and subsequent regrowth in the retina are delineated, using morphological measurements and immunofluorescent staining for dendritic and synaptic markers.

Deubiquitinase CYLD regulates excitatory synaptic transmission and short-term plasticity in the hippocampus.

The fate of proteins is determined by the addition of various forms of polyubiquitin during ubiquitin-mediated proteasomal degradation. Cylindromatosis (CYLD), a K63-specific deubiquitinase, is enriched in postsynaptic density fractions of the rodent central nervous system (CNS), but the synaptic role of CYLD in the CNS is poorly understand. Here we show that CYLD deficiency (Cyld-/-) results in reduced intrinsic hippocampal neuronal firing, a decrease in the frequency of spontaneous excitatory postsynaptic currents and a decrease in the amplitude of field excitatory postsynaptic potentials. Moreover, Cyld-/- hippocampus shows downregulated levels of presynaptic vesicular glutamate transporter 1 (vGlut1) and upregulated levels of postsynaptic GluA1, a subunit of the AMPA receptor, together with an altered paired-pulse ratio (PPR). We also found increased activation of astrocytes and microglia in the hippocampus of Cyld-/- mice. The present study suggests a critical role for CYLD in mediating hippocampal neuronal and synaptic activity.

[Remodeling of Neuronal Circuits in Chronic Pain].

Chronic pain is associated with various brain malfunctions, such as allodynia and anxiety. The underlying mechanism is a long-term alteration of neural circuits in the related brain regions. Here, we focus on the contribution of glial cells to build up pathological circuits. In addition, an attempt to enhance the neuronal plasticity of the pathological circuits to repair them to relieve abnormal pain will be introduced. The possible clinical applications will also be discussed.

Genetic Background Influence on Hippocampal Synaptic Plasticity: Frequency-Dependent Variations between an Inbred and an Outbred Mice Strain.

For almost half a century, acute hippocampal slice preparations have been widely used to investigate anti-amnesic (or promnesic) properties of drug candidates on long-term potentiation (LTP)-a cellular substrate that supports some forms of learning and memory. The large variety of transgenic mice models now available makes the choice of the genetic background when designing experiments crucially important. Furthermore, different behavioral phenotypes were reported between inbred and outbred strains. Notably, some differences in memory performance were emphasized. Despite this, investigations, unfortunately, did not explore electrophysiological properties. In this study, two stimulation paradigms were used to compare LTP in the hippocampal CA1 area of both inbred (C57BL/6) and outbred (NMRI) mice. High-frequency stimulation (HFS) revealed no strain difference, whereas theta-burst stimulation (TBS) resulted in significantly reduced LTP magnitude in NMRI mice. Additionally, we demonstrated that this reduced LTP magnitude (exhibited by NMRI mice) was due to lower responsiveness to theta-frequency during conditioning stimuli. In this paper, we discuss the anatomo-functional correlates that may explain such hippocampal synaptic plasticity divergence, although straightforward evidence is still lacking. Overall, our results support the prime importance of considering the animal model related to the intended electrophysiological experiments and the scientific issues to be addressed.

Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis.

Recent evidence has supported the hypothesis that amyotrophic lateral sclerosis (ALS) is a multi-step disease, as the onset of symptoms occurs after sequential exposure to a defined number of risk factors. Despite the lack of precise identification of these disease determinants, it is known that genetic mutations may contribute to one or more of the steps leading to ALS onset, the remaining being linked to environmental factors and lifestyle. It also appears evident that compensatory plastic changes taking place at all levels of the nervous system during ALS etiopathogenesis may likely counteract the functional effects of neurodegeneration and affect the timing of disease onset and progression. Functional and structural events of synaptic plasticity probably represent the main mechanisms underlying this adaptive capability, causing a significant, although partial and transient, resiliency of the nervous system affected by a neurodegenerative disease. On the other hand, the failure of synaptic functions and plasticity may be part of the pathological process. The aim of this review was to summarize what it is known today about the controversial involvement of synapses in ALS etiopathogenesis, and an analysis of the literature, although not exhaustive, confirmed that synaptic dysfunction is an early pathogenetic process in ALS. Moreover, it appears that adequate modulation of structural and functional synaptic plasticity may likely support function sparing and delay disease progression.

Visual Cortical Plasticity: Molecular Mechanisms as Revealed by Induction Paradigms in Rodents.

Assessing the molecular mechanism of synaptic plasticity in the cortex is vital for identifying potential targets in conditions marked by defective plasticity. In plasticity research, the visual cortex represents a target model for intense investigation, partly due to the availability of different in vivo plasticity-induction protocols. Here, we review two major protocols: ocular-dominance (OD) and cross-modal (CM) plasticity in rodents, highlighting the molecular signaling pathways involved. Each plasticity paradigm has also revealed the contribution of different populations of inhibitory and excitatory neurons at different time points. Since defective synaptic plasticity is common to various neurodevelopmental disorders, the potentially disrupted molecular and circuit alterations are discussed. Finally, new plasticity paradigms are presented, based on recent evidence. Stimulus-selective response potentiation (SRP) is one of the paradigms addressed. These options may provide answers to unsolved neurodevelopmental questions and offer tools to repair plasticity defects.

Gender and Neurosteroids: Implications for Brain Function, Neuroplasticity and Rehabilitation.

Neurosteroids are synthesized de novo in the nervous system; they mainly moderate neuronal excitability, and reach target cells via the extracellular pathway. The synthesis of neurosteroids occurs in peripheral tissues such as gonads tissues, liver, and skin; then, because of their high lipophilia, they cross the blood-brain barrier and are stored in the brain structure. Neurosteroidogenesis occurs in brain regions such as the cortex, hippocampus, and amygdala by enzymes necessary for the in situ synthesis of progesterone from cholesterol. Neurosteroids could be considered the main players in both sexual steroid-induced hippocampal synaptic plasticity and normal transmission in the hippocampus. Moreover, they show a double function of increasing spine density and enhancing long term potentiation, and have been related to the memory-enhancing effects of sexual steroids. Estrogen and progesterone affect neuronal plasticity differently in males and females, especially regarding changes in the structure and function of neurons in different regions of the brain. Estradiol administration in postmenopausal women allowed for improving cognitive performance, and the combination with aerobic motor exercise seems to enhance this effect. The paired association between rehabilitation and neurosteroids treatment could provide a boosting effect in order to promote neuroplasticity and therefore functional recovery in neurological patients. The aim of this review is to investigate the mechanisms of action of neurosteroids as well as their sex-dependent differences in brain function and their role in neuroplasticity and rehabilitation.

Elevated Hippocampal CRMP5 Mediates Chronic Stress-Induced Cognitive Deficits by Disrupting Synaptic Plasticity, Hindering AMPAR Trafficking, and Triggering Cytokine Release.

Chronic stress is a critical risk factor for developing depression, which can impair cognitive function. However, the underlying mechanisms involved in chronic stress-induced cognitive deficits remain unclear. Emerging evidence suggests that collapsin response mediator proteins (CRMPs) are implicated in the pathogenesis of psychiatric-related disorders. Thus, the study aims to examine whether CRMPs modulate chronic stress-induced cognitive impairment. We used the chronic unpredictable stress (CUS) paradigm to mimic stressful life situations in C57BL/6 mice. In this study, we found that CUS-treated mice exhibited cognitive decline and increased hippocampal CRMP2 and CRMP5 expression. In contrast to CRMP2, CRMP5 levels strongly correlated with the severity of cognitive impairment. Decreasing hippocampal CRMP5 levels through shRNA injection rescued CUS-induced cognitive impairment, whereas increasing CRMP5 levels in control mice exacerbated memory decline after subthreshold stress treatment. Mechanistically, hippocampal CRMP5 suppression by regulating glucocorticoid receptor phosphorylation alleviates chronic stress-induced synaptic atrophy, disruption of AMPA receptor trafficking, and cytokine storms. Our findings show that hippocampal CRMP5 accumulation through GR activation disrupts synaptic plasticity, impedes AMPAR trafficking, and triggers cytokine release, thus playing a critical role in chronic stress-induced cognitive deficits.

Harnessing neuroplasticity to improve motor performance in infants with cerebral palsy: a study protocol for the GAME randomised controlled trial.

INTRODUCTION: Cerebral palsy (CP) is the most common physical disability of childhood worldwide. Historically the diagnosis was made between 12 and 24 months, meaning data about effective early interventions to improve motor outcomes are scant. In high-income countries, two in three children will walk. This evaluator-blinded randomised controlled trial will investigate the efficacy of an early and sustained Goals-Activity-Motor Enrichment approach to improve motor and cognitive skills in infants with suspected or confirmed CP. METHODS AND ANALYSIS: Participants will be recruited from neonatal intensive care units and the community in Australia across four states. To be eligible for inclusion infants will be aged 3-6.5 months corrected for prematurity and have a diagnosis of CP or 'high risk of CP' according to the International Clinical Practice Guideline criteria. Eligible participants whose caregivers consent will be randomly allocated to receive usual care or weekly sessions at home from a GAME-trained study physiotherapist or occupational therapist, paired with a daily home programme, until age 2. The study requires 150 participants per group to detect a 0.5 SD difference in motor skills at 2 years of age, measured by the Peabody Developmental Motor Scales-2. Secondary outcomes include gross motor function, cognition, functional independence, social-emotional development and quality of life. A within-trial economic evaluation is also planned. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Sydney Children's Hospital Network Human Ethics Committee in April 2017 (ref number HREC/17/SCHN/37). Outcomes will be disseminated through peer-reviewed journal publications, presentations at international conferences and consumer websites. TRIAL REGISTRATION NUMBER: ACTRN12617000006347.

Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer's disease.

Calcium dynamics in astrocytes represent a fundamental signal that through gliotransmitter release regulates synaptic plasticity and behaviour. Here we present a longitudinal study in the PS2APP mouse model of Alzheimer's disease (AD) linking astrocyte Ca2+ hypoactivity to memory loss. At the onset of plaque deposition, somatosensory cortical astrocytes of AD female mice exhibit a drastic reduction of Ca2+ signaling, closely associated with decreased endoplasmic reticulum Ca2+ concentration and reduced expression of the Ca2+ sensor STIM1. In parallel, astrocyte-dependent long-term synaptic plasticity declines in the somatosensory circuitry, anticipating specific tactile memory loss. Notably, we show that both astrocyte Ca2+ signaling and long-term synaptic plasticity are fully recovered by selective STIM1 overexpression in astrocytes. Our data unveil astrocyte Ca2+ hypoactivity in neocortical astrocytes as a functional hallmark of early AD stages and indicate astrocytic STIM1 as a target to rescue memory deficits.

The dysfunctionality of hippocampal synapses may be directly related to PM-induced impairments in spatial learning and memory in juvenile rats.

Epidemiological studies have demonstrated that exposure to air particulate matter (PM) increases the incidence of cardiovascular and respiratory diseases and exerts a significant neurotoxic effect on the nervous system, especially on the immature nervous system. Here, we selected PND28 rats to simulate the immature nervous system of young children and used neurobehavioral methods to examine how exposure to PM affected spatial learning and memory, as well as electrophysiology, molecular biology, and bioinformatics to study the morphology of hippocampus and the function of hippocampal synapses. We discovered that spatial learning and memory were impaired in rats exposed to PM. The morphology and structure of the hippocampus were altered in the PM group. In addition, after exposure to PM, the relative expression of synaptophysin (SYP) and postsynaptic density 95 (PSD95) proteins decreased dramatically in rats. Furthermore, PM exposure impaired long-term potentiation (LTP) in the hippocampal Schaffer-CA1 pathway. Interestingly, RNA sequencing and bioinformatics analysis revealed that the differentially expressed genes (DEGs) were rich in terms associated with synaptic function. Five hub genes (Agt, Camk2a, Grin2a, Snca, and Syngap1) that may play a significant role in the dysfunctionality of hippocampal synapses were identified. Our findings implied that exposure to PM impaired spatial learning and memory via exerting impacts on the dysfunctionality of hippocampal synapses in juvenile rats and that Agt, Camk2a, Grin2a, Snca, and Syngap1 may drive PM-caused synaptic dysfunction.

Microstructural and neurochemical plasticity mechanisms interact to enhance human perceptual decision-making.

Experience and training are known to boost our skills and mold the brain's organization and function. Yet, structural plasticity and functional neurotransmission are typically studied at different scales (large-scale networks, local circuits), limiting our understanding of the adaptive interactions that support learning of complex cognitive skills in the adult brain. Here, we employ multimodal brain imaging to investigate the link between microstructural (myelination) and neurochemical (GABAergic) plasticity for decision-making. We test (in males, due to potential confounding menstrual cycle effects on GABA measurements in females) for changes in MRI-measured myelin, GABA, and functional connectivity before versus after training on a perceptual decision task that involves identifying targets in clutter. We demonstrate that training alters subcortical (pulvinar, hippocampus) myelination and its functional connectivity to visual cortex and relates to decreased visual cortex GABAergic inhibition. Modeling interactions between MRI measures of myelin, GABA, and functional connectivity indicates that pulvinar myelin plasticity interacts-through thalamocortical connectivity-with GABAergic inhibition in visual cortex to support learning. Our findings propose a dynamic interplay of adaptive microstructural and neurochemical plasticity in subcortico-cortical circuits that supports learning for optimized decision-making in the adult human brain.