Neuronal Functional Connectivity Research Articles

Inferring neuronal network functional connectivity with directed information

A major challenge in neuroscience is to develop effective tools that infer the circuit connectivity from large-scale recordings of neuronal activity patterns. In this study, context tree maximizing (CTM) was used to estimate directed information (DI), which measures causal influences among neural spike trains in order to infer putative synaptic connections. In contrast to existing methods, the method presented here is data driven and can readily identify both linear and nonlinear relations between neurons. This CTM-DI method reliably identified circuit structures underlying simulations of realistic conductance-based networks. It also inferred circuit properties from voltage-sensitive dye recordings of the buccal ganglion of Aplysia. This method can be applied to other large-scale recordings as well. It offers a systematic tool to map network connectivity and to track changes in network structure such as synaptic strengths as well as the degrees of connectivity of individual neurons, which in turn could provide insights into how modifications produced by learning are distributed in a neural network.NEW & NOTEWORTHY This study brings together the techniques of voltage-sensitive dye recording and information theory to infer the functional connectome of the feeding central pattern generating network of Aplysia. In contrast to current statistical approaches, the inference method developed in this study is data driven and validated by conductance-based model circuits, can distinguish excitatory and inhibitory connections, is robust against synaptic plasticity, and is capable of detecting network structures that mediate motor patterns.

Application of Carbon Nanotubes for Controlled Release of Growth Factors or Endocannabinoids: A Breakthrough in Biomedicine

Carbon nanotubes, the nanostructures with immense potential in various scientific fields such as the regenerative medicine, have emerged as innovative nanosreservoirs with multimodal functionality and application in theranostic sessions. The superior mechanical properties, high thermoelectrical conductivities, or improved solubility and biocompatibility have made CNTs as suitable candidates for biosensing, high-resolution imaging, tissue-engineering, and delivery of a variety of compounds with poor solubility or short half-life. These advanced nanovectors which promote neuronal growth and functional connectivity, have shown great theranostic potential in the central nervous system disorders. Several pioneering works have shown the ability of CNTs for controlled release of drugs or growth factors into the brain. Over the last decade the neurotropic and metabotrophic effects of nerve-growth factor, brain-derived neurothropic factor and endocannabinoid system and their involvement in the mechanism of action of a wide variety of drugs have been the focus of intense research. In order to overcome the rapid degradation and/or non-specific distribution of nerve-growth factor or endocanabinoids, conjugation with CNTs has led to the prolonged effects of these modulating factors. Based on their unique properties, the appropriate application of functionalized CNTs may indeed revolutionize the current biomedical interventions that has been highlighted in the present review.

Disrupted Causal Connectivity Anchored in the Posterior Cingulate Cortex in Amnestic Mild Cognitive Impairment.

Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal cognitive aging and Alzheimer’s disease. Previous studies have found that neuronal activity and functional connectivity impaired in many functional networks, especially in the default mode network (DMN), which is related to significantly impaired cognitive and memory functions in aMCI patients. However, few studies have focused on the effective connectivity of the DMN and its subsystems in aMCI patients. The posterior cingulate cortex (PCC) is considered a crucial region in connectivity of the DMN and its key subsystem. In this study, using the coefficient Granger causality analysis approach and using the PCC as the region of interest, we explored changes in the DMN and its subsystems in effective connectivity with other brain regions as well as in correlations among them in 16 aMCI patients and 15 age-matched cognitively normal elderly. Results showed decreased effective connectivity from PCC to whole brain in the left prefrontal cortex, the left medial temporal lobe (MTL), the left fusiform gyrus (FG), and the left cerebellar hemisphere, meanwhile, right temporal lobe showed increased effective connectivity from PCC to the whole brain in aMCI patients compared with normal control. In addition, compared with the normal controls, increased effective connectivity of the whole brain to the PCC in aMCI patients was found in the right thalamus, left medial temporal lobe, left FG, and left cerebellar hemisphere. Compared with the normal controls, no reduced effective connectivity was found in any brain regions from the whole brain to the PCC in aMCI patients. The reduced effective connectivity of the PCC to left MTL showed negative correlation trend with neuropsychological tests (Auditory Verbal Learning Test-immediate recall and clock drawing test) in aMCI patients. Our study shows that aMCI patients have abnormalities in effective connectivity within the PCC-centered DMN network and its posterior subsystems as well as in the cerebellar hemisphere and thalamus. Abnormal integration of networks may be related to cognitive and memory impairment and compensation mechanisms in aMCI patients.

Functional Connectivity of Basolateral Amygdala Neurons Carrying Orexin Receptors and Melanin-concentrating Hormone Receptors in Regulating Sociability and Mood-related Behaviors

Chronic stress induces changes in neuronal functions in specific brain regions regulating sociability and mood-related behaviors. Recently we reported that stress-induced persistent upregulation of the neuropeptides orexin and melanin-concentrating hormone (MCH) in the basolateral amygdala (BLA) and the resulting activation of orexin receptors or MCH receptors within the BLA produced deficits in sociability and mood-related behaviors. In the present study, we investigated the neural targets that were innervated by BLA neurons containing orexin receptors or MCH receptors. The viral vector system AAV2-CaMKII-ChR2-eYFP was injected into the BLA to trace the axonal tracts of BLA neurons. This axon labeling analysis led us to identify the prelimbic and infralimbic cortices, nucleus accumbens (NAc), dorsal striatum, paraventricular nucleus (PVN), interstitial nucleus of the posterior limb of the anterior commissure, habenula, CA3 pyramidal neurons, central amygdala, and ventral hippocampus as the neuroanatomical sites receiving synaptic inputs of BLA neurons. Focusing on these regions, we then carried out stimulus-dependent c-Fos induction analysis after activating orexin receptors or MCH receptors of BLA neurons. Stereotaxic injection of an orexin receptor agonist or an MCH receptor agonist in the BLA induced c-Fos expression in the NAc, PVN, central amygdala, ventral hippocampus, lateral habenula and lateral hypothalamus, which are all potentially important for depression-related behaviors. Among these neural correlates, the NAc, PVN and central amygdala were strongly activated by stimulation of orexin receptors or MCH receptors in the BLA, whereas other BLA targets were differentially and weakly activated. These results identify a functional connectivity of BLA neurons regulated by orexin and MCH receptor systems in sociability and mood-related behaviors.

Functional MRI signal fluctuations highlight altered resting brain activity in Huntington's disease.

The fractional Amplitude of Low Frequency Fluctuations (fALFF) and the degree of local synchronization (Regional Homogeneity - ReHo) of resting-state BOLD signal have been suggested to map spontaneous neuronal activity and local functional connectivity, respectively. We compared voxelwise, independent of atrophy, the fALFF and ReHo patterns of 11 presymptomatic (ps-HD) and 28 symptomatic (sHD) Huntington's disease mutation carriers, with those of 40 normal volunteers, and tested their possible correlations with the motor and cognitive subscores of the Unified Huntington's Disease Rating Scale. In sHD patients, fALFF was mainly reduced bilaterally in parietal lobes (right precuneus being already affected in psHD), and in superior frontal gyri, and increased bilaterally in cerebellar lobules VI, VIII and IX, as well as in the right inferior temporal gyrus. In sHD, and to a lesser extent in psHD, ReHo was bilaterally reduced in putamina, cerebellar lobules III to VI, and superior medial frontal gyri, and increased in both psHD and sHD in fronto-basal cortices, and in the right temporal lobe. fALFF correlated inversely with cognitive scores in lobule IX of the cerebellum (mainly with total Stroop score, p<0.0001), and in the medial portions of both thalami. These results are consistent with a reduced neuronal activity in the cortical components of the executive networks, known to be affected in Huntington's Disease, and with reduced local functional integration in subcortical and cerebellar components of the sensori-motor network. Cerebellar clusters of significant correlation of fALFF with executive function scores may be related to compensatory mechanisms.

Uses, misuses, new uses and fundamental limitations of magnetic resonance imaging in cognitive science.

When blood oxygenation level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) was discovered in the early 1990s, it provoked an explosion of interest in exploring human cognition, using brain mapping techniques based on MRI. Standards for data acquisition and analysis were rapidly put in place, in order to assist comparison of results across laboratories. Recently, MRI data acquisition capabilities have improved dramatically, inviting a rethink of strategies for relating functional brain activity at the systems level with its neuronal substrates and functional connections. This paper reviews the established capabilities of BOLD contrast fMRI, the perceived weaknesses of major methods of analysis, and current results that may provide insights into improved brain modelling. These results have inspired the use of in vivo myeloarchitecture for localizing brain activity, individual subject analysis without spatial smoothing and mapping of changes in cerebral blood volume instead of BOLD activation changes. The apparent fundamental limitations of all methods based on nuclear magnetic resonance are also discussed.This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Statistical Learning of Neuronal Functional Connectivity

Identifying the network structure of a neuron ensemble beyond the standard measure of pairwise correlations is critical for understanding how information is transferred within such a neural population. However, the spike train data pose significant challenges to conventional statistical methods due to not only the complexity, massive size, and large scale, but also high dimensionality. In this article, we propose a novel “structural information enhanced” (SIE) regularization method for estimating the conditional intensities under the generalized linear model (GLM) framework to better capture the functional connectivity among neurons. We study the consistency of parameter estimation of the proposed method. A new “accelerated full gradient update” algorithm is developed to efficiently handle the complex penalty in the SIE-GLM for large sparse datasets applicable to spike train data. Simulation results indicate that our proposed method outperforms existing approaches. An application of the proposed method to a real spike train dataset, obtained from the prelimbic region of the prefrontal cortex of adult male rats when performing a T-maze based delayed-alternation task of working memory, provides some insight into the neuronal network in that region.

From genes to treatment: The effect of polymorphisms in neurotransmitter systems on addictive behaviour, neural response and relapse

IntroductionThe development and maintenance of an alcohol addiction is a complex interaction between genetic and environmental factors. Genetic effects seem to contribute substantially to the risk of developing an addiction, but also to its course and patients’ responses to different treatments. Recent studies identified associations between polymorphisms in the genes of glutamate and μ-opioid receptors and addiction risk. Those receptors are of special interest, because they are targets of therapeutic agents, such as acamprosate and topiramate.Objectives and aimsSeveral studies were conducted, in order to further determine the effects of genetic polymorphisms in glutamate and opioid receptor genes on addictive behavior, neural response to alcohol cues and relapse risk.MethodsGenetic effects were investigated in samples of alcohol-dependent patients using functional imaging techniques, neuropsychological tests and follow-up investigation after standard clinical treatment. Data on clinical parameters, neuronal response to alcohol cues, functional neuronal connectivity and relapse risk were collected and analyzed.ResultsResults demonstrate effects of genetic polymorphisms in glutamate and opioid receptors on neuronal response to alcohol cues in frontal and mesolimbic brain areas, subjective craving and time to first relapse. Current findings will be discussed in the light of existing evidence on the contribution of genetic effects to treatment outcome and patient stratification.ConclusionsThe investigation of genetic risk factors and mechanisms by which they affect addiction related phenotypes seems to be a promising tool to identify molecular treatment targets and predictors for successful treatment strategies.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Modulation of gamma and alpha spinal motor neurons activity by trans-spinal direct current stimulation: effects on reflexive actions and locomotor activity.

Spontaneous and evoked spinal activities interact to set the characteristics of emergent motor responses. Gamma motor neurons have feedforward and feedback functions in motor control, which are crucial for transforming motor commands into action. Meanwhile, the intrinsic excitability and functional connectivity of alpha motor neurons determine the accuracy of actions. In this study, we investigated the effects of trans-spinal direct current stimulation (tsDCS) on spontaneous and cortically evoked activity of well-isolated single units of gamma and alpha motor neurons in mice. We also investigated the effects of tsDCS on reflexive and locomotor actions. In general, motor neurons showed increased responses to cathodal tsDCS (c-tsDCS) and decreased responses to anodal tsDCS (a-tsDCS). These effects were observed for cortically evoked discharges and spontaneous firing rates of gamma motor neurons, cortically evoked discharges of larger alpha motor neurons, and spontaneous firing rates of smaller alpha motor neurons. An exception was that spontaneous firing rates of larger alpha motor neurons showed the opposite pattern of reduction by c-tsDCS and increase by a-tsDCS. Reflexive and voluntary behavior were also increased by c-tsDCS and reduced by a-tsDCS. Specifically, the amplitude and duration of crossed and tail pinch reflexes in decerebrate animals and the quality of ground and treadmill walking patterns in healthy awake animals showed this pattern. These polarity-specific changes in behavior could be attributed to polarity-mediated modulation of alpha and gamma motor neuron activity and spinal circuitry. The results reveal an important principle: effects of tsDCS on spinal motor neurons depend on current polarity and cell size.

Impaired Functional Connectivity in the Prefrontal Cortex: A Mechanism for Chronic Stress-Induced Neuropsychiatric Disorders.

Chronic stress-related psychiatric diseases, such as major depression, posttraumatic stress disorder, and schizophrenia, are characterized by a maladaptive organization of behavioral responses that strongly affect the well-being of patients. Current evidence suggests that a functional impairment of the prefrontal cortex (PFC) is implicated in the pathophysiology of these diseases. Therefore, chronic stress may impair PFC functions required for the adaptive orchestration of behavioral responses. In the present review, we integrate evidence obtained from cognitive neuroscience with neurophysiological research with animal models, to put forward a hypothesis that addresses stress-induced behavioral dysfunctions observed in stress-related neuropsychiatric disorders. We propose that chronic stress impairs mechanisms involved in neuronal functional connectivity in the PFC that are required for the formation of adaptive representations for the execution of adaptive behavioral responses. These considerations could be particularly relevant for understanding the pathophysiology of chronic stress-related neuropsychiatric disorders.

Recent Advances in Autism Spectrum Disorders: Applications of Whole Exome Sequencing Technology.

Autism spectrum disorders (ASD) is characterized by three core symptoms with impaired reciprocal social interaction and communication, a pattern of repetitive behavior and/or restricted interests in early childhood. The prevalence is higher in male children than in female children. As a complex neurodevelopmental disorder, the phenotype and severity of autism are extremely heterogeneous with differences from one patient to another. Genetics has a key role in the etiology of autism. Environmental factors are also interacting with the genetic profile and cause abnormal changes in neuronal development, brain growth, and functional connectivity. The term of exome represents less than 1% of the human genome, but contains 85% of known disease-causing variants. Whole-exome sequencing (WES) is an application of the next generation sequencing technology to determine the variations of all coding regions, or exons of known genes. For this reason, WES has been extensively used for clinical studies in the recent years. WES has achieved great success in the past years for identifying Mendelian disease genes. This review evaluates the potential of current findings in ASD for application in next generation sequencing technology, particularly WES. WES and whole-genome sequencing (WGS) approaches may lead to the discovery of underlying genetic factors for ASD and may thereby identify novel therapeutic targets for this disorder.

Relating functional connectivity in V1 neural circuits and 3D natural scenes using Boltzmann machines

Bayesian theory has provided a compelling conceptualization for perceptual inference in the brain. Central to Bayesian inference is the notion of statistical priors. To understand the neural mechanisms of Bayesian inference, we need to understand the neural representation of statistical regularities in the natural environment. In this paper, we investigated empirically how statistical regularities in natural 3D scenes are represented in the functional connectivity of disparity-tuned neurons in the primary visual cortex of primates. We applied a Boltzmann machine model to learn from 3D natural scenes, and found that the units in the model exhibited cooperative and competitive interactions, forming a “disparity association field”, analogous to the contour association field. The cooperative and competitive interactions in the disparity association field are consistent with constraints of computational models for stereo matching. In addition, we simulated neurophysiological experiments on the model, and found the results to be consistent with neurophysiological data in terms of the functional connectivity measurements between disparity-tuned neurons in the macaque primary visual cortex. These findings demonstrate that there is a relationship between the functional connectivity observed in the visual cortex and the statistics of natural scenes. They also suggest that the Boltzmann machine can be a viable model for conceptualizing computations in the visual cortex and, as such, can be used to predict neural circuits in the visual cortex from natural scene statistics.

Disrupted amplitude of low-frequency fluctuations in antipsychotic-naïve adolescents with early-onset schizophrenia

Evidence points to a crucial role for altered neural oscillations and synchrony in the pathophysiology of schizophrenia. Previous resting state functional magnetic resonance imaging (fMRI) studies found aberrant amplitudes of low-frequency oscillations in adult patients with schizophrenia. Whether the abnormality is also present in adolescents with early-onset schizophrenia (EOS) is largely unknown. We recruited 39 adolescents with a first episode of EOS and 31 age- and education- matched healthy controls. Resting state fMRI was obtained using an echo-planar imaging sequence. Voxel-wise amplitude of low-frequency (0.01–0.08Hz) fluctuations (ALFF) was compared between groups. We investigated seed-based functional connectivity between significantly disturbed ALFF regions and whole brain voxels in all participants. EOS participants exhibited significantly increased ALFF values in the orbitofrontal cortex (OFC) and decreased ALFF in the ventral precuneus compared with controls. Decreased ALFF values in the precuneus of EOS showed a significant negative correlation with negative symptom scores on the Positive and Negative Syndrome Scale. Disturbed functional connectivity mainly occurred between the orbitofrontal cortex and the temporal cortex in EOS. These findings demonstrate abnormal spontaneous neuronal activity and functional connectivity in the frontal and parietal cortex of EOS. Aberrant ALFF in the precuneus might be a biomarker of EOS.

Aberrant Neuronal Activity and Dysfunctional Connectivity in Aβ1-42- mediated Memory Deficits in Rats.

Alzheimer's disease (AD) is a neurodegenerative disorder that gradually induces cognitive deficit. Working memory deficits have been previously reported in AD and Amyloid-β peptide (Aβ) is regarded as a causative factor for the impairments. Accumulating evidence has identified that neuronal ensemble activity as well as functional connectivity among neurons encode and process information in normal brain. How Aβ contributes to the abnormal neuronal ensemble activity and corresponding functional connectivity which, in turn, leads to the cognitive deficits? To address the issue, we simultaneously recorded neuronal activity from medial prefrontal cortex of rats (control and Aβ injected group) when the rats performed a Y-maze working memory task, to investigate the properties of neuronal ensemble activity and functional connectivity. In the control group, a group of neurons were collectively activated and the connectivity among the neurons strengthened during the working memory task. However, in the Aβ group, the neuronal activity and connectivity never experience significant change. Our results indicate that the dysfunction of neuronal activity and connectivity may provide insight for the Aβ-induced working memory deficits.

Spontaneous brain activity following fear reminder of fear conditioning by using resting-state functional MRI.

Although disrupting reconsolidation may be a promising approach to attenuate or erase the expression of fear memory, it is not clear how the neural state following fear reminder contribute to the following fear extinction. To address this question, we used resting-state functional magnetic resonance imaging (rs-fMRI) to measure spontaneous neuronal activity and functional connectivity (RSFC) following fear reminder. Some brain regions such as dorsal anterior cingulate (dACC) and ventromedial prefrontal cortex (vmPFC) showed increased amplitude of LFF (ALFF) in the fear reminder group than the no reminder group following fear reminder. More importantly, there was much stronger functional connectivity between the amygdala and vmPFC in the fear reminder group than those in the no reminder group. These findings suggest that the strong functional connectivity between vmPFC and amygdala following a fear reminder could serve as a key role in the followed-up fear extinction stages, which may contribute to the erasing of fear memory.

Electrophysiological Assessment of Serotonin and GABA Neuron Function in the Dorsal Raphe during the Third Trimester Equivalent Developmental Period in Mice.

Alterations in the development of the serotonin system can have prolonged effects, including depression and anxiety disorders later in life. Serotonin axonal projections from the dorsal raphe undergo extensive refinement during the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy). However, little is known about the functional properties of serotonin and GABA neurons in the dorsal raphe during this critical developmental period. We assessed the functional properties and synaptic connectivity of putative serotoninergic neurons and GABAergic neurons in the dorsal raphe during early [postnatal day (P) P5–P7] and late (P15–P17) stages of the third trimester equivalent period using electrophysiology. Our studies demonstrate that GABAergic neurons are hyperexcitable at P5–P7 relative to P15–P17. Furthermore, putative serotonin neurons exhibit an increase in both excitatory and GABAA receptor-mediated spontaneous postsynaptic currents during this developmental period. Our data suggest that GABAergic neurons and putative serotonin neurons undergo significant electrophysiological changes during neonatal development.

Antidepressant drug action--From rapid changes on network function to network rewiring.

There has been significant recent progress in understanding the neurobiological mechanisms of antidepressant treatments. The delayed-onset of action of monoamine-based antidepressant drugs have been associated to their ability to slowly increase synaptic plasticity and neuronal excitability via altering neurotrophic signaling (synthesis of BDNF and activation of its receptor TrkB), dematuration of GABAergic interneurons and inhibition of "breaks of plasticity". On the other hand, antidepressants rapidly regulate emotional processing that - with the help of heightened plasticity and appropriate rehabilitation - gradually lead to significant changes on functional neuronal connectivity and clinical recovery. Moreover, the discovery of rapid-acting antidepressants, most notably ketamine, has inspired interest for novel antidepressant developments with better efficacy and faster onset of action. Therapeutic effects of rapid-acting antidepressants have been linked with their ability to rapidly regulate neuronal excitability and thereby increase synaptic translation and release of BDNF, activation of the TrkB-mTOR-p70S6k signaling pathway and increased synaptogenesis within the prefrontal cortex. Thus, alterations in TrkB signaling, synaptic plasticity and neuronal excitability are shared neurobiological phenomena implicated in antidepressant responses produced by both gradually and rapid acting antidepressants. However, regardless of antidepressant, their therapeutic effects are not permanent which suggests that their effects on neuronal connectivity and network function remain unstable and vulnerable for psychosocial challenges.

Manganese-Enhanced MRI Reflects Both Activity-Independent and Activity-Dependent Uptake within the Rat Habenulomesencephalic Pathway.

Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful technique for assessing the functional connectivity of neurons within the central nervous system. Despite the widely held proposition that MEMRI signal is dependent on neuronal activity, few studies have directly tested this implicit hypothesis. In the present series of experiments, MnCl2 was injected into the habenula of urethane-anesthetized rats alone or in combination with drugs known to alter neuronal activity by modulating specific voltage- and/or ligand-gated ion channels. Continuous quantitative T1 mapping was used to measure Mn2+ accumulation in the interpeduncular nucleus, a midline structure in which efferents from the medial habenula terminate. Microinjection of MnCl2 into the habenular complex using a protocol that maintained spontaneous neuronal activity resulted in a time-dependent increase in MEMRI signal intensity in the interpeduncular nucleus consistent with fast axonal transport of Mn2+ between these structures. Co-injection of the excitatory amino-acid agonist AMPA, increased the Mn2+-enhanced signal intensity within the interpeduncular nucleus. AMPA-induced increases in MEMRI signal were attenuated by co-injection of either the sodium channel blocker, TTX, or broad-spectrum Ca2+ channel blocker, Ni2+, and were occluded in the presence of both channel blockers. However, neither Ni2+ nor TTX, alone or in combination, attenuated the increase in signal intensity following injection of Mn2+ into the habenula. These results support the premise that changes in neuronal excitability are reflected by corresponding changes in MEMRI signal intensity. However, they also suggest that basal rates of Mn2+ uptake by neurons in the medial habenula may also occur via activity-independent mechanisms.

A novel function for Wnt signaling modulating neuronal firing activity and the temporal structure of spontaneous oscillation in the entorhinal–hippocampal circuit

During early and late postnatal developments, the establishment of functional neuronal connectivity depends on molecules like Wnt that help the recently formed synapses to establish and consolidate their new cellular interactions. However, unlike other molecules, whether Wnt can modulate the firing properties of cells is unknown. Here, for the first time we explore the physiological effect of the canonical and non-canonical Wnt pathways on a circuit that is currently generating oscillatory activity, the entorhinal cortex–hippocampal circuit. Our results indicate that Wnt pathways have strong influence in the circuital and cellular properties depending on the Wnt protein isoforms, concentration, and type of neuronal circuit. Antibodies against canonical and non-canonical ligands, as well as WASP-1 and sFRP-2, demonstrate that constitutive release of Wnts contributes to the maintenance of the network and intrinsic properties of the circuit. Furthermore, we found that the excess of Wnt3a or the permanent intracellular activation of the pathway with BIO-6 accelerates the period of the oscillation by disrupting the oscillatory units (Up states) in short units, presumably by affecting the synaptic mechanisms that couples neurons into the oscillatory cycle, but without affecting the spike generation. Instead, low doses of Wnt5a increase the period of the oscillation in EC by incorporating new cells into the network activity, probably modifying firing activity in other places of the circuit. Moreover, we found that Wnt signaling operates under different principles in the hippocampus. Using pyrvinium pamoate, a Wnt/β-catenin dependent pathway inhibitor, we demonstrated that this pathway is essential to keep the firing activity in the circuit CA3, and in less degree of CA1 circuit. However, CA1 circuit possesses homeostatic mechanisms to up-regulate the firing activity when it has been suppressed in CA3, and to down-modulate the cellular excitability when exacerbated circuital activity has dominated. In summary, the amount of Wnt that is being released can exert a fine tuning of the physiological output, modulating firing activity, improving reliability of communication between neurons, and maintaining a continuous self-regulatory cycle of synaptic structure–function that can be present during all postnatal life.

Technical considerations for functional magnetic resonance imaging analysis.

Clinical application of functional magnetic resonance imaging (fMRI) based on blood oxygenation level-dependent (BOLD) effect has increased over the past decade because of its ability to map regional blood flow in response to brain stimulation. This mapping is primarily achieved by exploiting the BOLD effect precipitated by changes in the magnetic properties of hemoglobin. BOLD fMRI has utility in neurosurgical planning and mapping neuronal functional connectivity. Conventional echo planar imaging techniques are used to acquire stimulus-driven fMR imaging BOLD data. This article highlights technical aspects of fMRI data analysis to make it more accessible in clinical settings.