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1.  Unique membrane properties and enhanced signal processing in human neocortical neurons 
eLife  null;5:e16553.
The advanced cognitive capabilities of the human brain are often attributed to our recently evolved neocortex. However, it is not known whether the basic building blocks of the human neocortex, the pyramidal neurons, possess unique biophysical properties that might impact on cortical computations. Here we show that layer 2/3 pyramidal neurons from human temporal cortex (HL2/3 PCs) have a specific membrane capacitance (Cm) of ~0.5 µF/cm2, half of the commonly accepted 'universal' value (~1 µF/cm2) for biological membranes. This finding was predicted by fitting in vitro voltage transients to theoretical transients then validated by direct measurement of Cm in nucleated patch experiments. Models of 3D reconstructed HL2/3 PCs demonstrated that such low Cm value significantly enhances both synaptic charge-transfer from dendrites to soma and spike propagation along the axon. This is the first demonstration that human cortical neurons have distinctive membrane properties, suggesting important implications for signal processing in human neocortex.
PMCID: PMC5100995  PMID: 27710767
compartmental modeling; human neurons; neurons computation; membrane properties; Human; Mouse
2.  Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex 
Cerebral Cortex (New York, NY)  2015;25(12):4839-4853.
The size and shape of dendrites and axons are strong determinants of neuronal information processing. Our knowledge on neuronal structure and function is primarily based on brains of laboratory animals. Whether it translates to human is not known since quantitative data on “full” human neuronal morphologies are lacking. Here, we obtained human brain tissue during resection surgery and reconstructed basal and apical dendrites and axons of individual neurons across all cortical layers in temporal cortex (Brodmann area 21). Importantly, morphologies did not correlate to etiology, disease severity, or disease duration. Next, we show that human L(ayer) 2 and L3 pyramidal neurons have 3-fold larger dendritic length and increased branch complexity with longer segments compared with temporal cortex neurons from macaque and mouse. Unsupervised cluster analysis classified 88% of human L2 and L3 neurons into human-specific clusters distinct from mouse and macaque neurons. Computational modeling of passive electrical properties to assess the functional impact of large dendrites indicates stronger signal attenuation of electrical inputs compared with mouse. We thus provide a quantitative analysis of “full” human neuron morphologies and present direct evidence that human neurons are not “scaled-up” versions of rodent or macaque neurons, but have unique structural and functional properties.
PMCID: PMC4635923  PMID: 26318661
3.  Sustained Attentional States Require Distinct Temporal Involvement of the Dorsal and Ventral Medial Prefrontal Cortex 
Attending the sensory environment for cue detection is a cognitive operation that occurs on a time scale of seconds. The dorsal and ventral medial prefrontal cortex (mPFC) contribute to separate aspects of attentional processing. Pyramidal neurons in different parts of the mPFC are active during cognitive behavior, yet whether this activity is causally underlying attentional processing is not known. We aimed to determine the precise temporal requirements for activation of the mPFC subregions during the seconds prior to cue detection. To test this, we used optogenetic silencing of dorsal or ventral mPFC pyramidal neurons at defined time windows during a sustained attentional state. We find that the requirement of ventral mPFC pyramidal neuron activity is strictly time-locked to stimulus detection. Inhibiting the ventral mPFC 2 s before or during cue presentation reduces response accuracy and hampers behavioral inhibition. The requirement for dorsal mPFC activity on the other hand is temporally more loosely related to a preparatory attentional state, and short lapses in pyramidal neuron activity in dorsal mPFC do not affect performance. This only occurs when the dorsal mPFC is inhibited during the entire preparatory period. Together, our results reveal that a dissociable temporal recruitment of ventral and dorsal mPFC is required during attentional processing.
PMCID: PMC5005373  PMID: 27630545
attention; dorsomedial prefrontal cortex; ventromedial prefrontal cortex; optogenetics; pyramidal neurons
4.  Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors 
Acetylcholine (ACh) signaling underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. Alterations in ACh signaling are involved in the pathophysiology of multiple neuropsychiatric disorders. In the central nervous system, ACh transmission is mainly guaranteed by dense innervation of select cortical and subcortical regions from disperse groups of cholinergic neurons within the basal forebrain (BF; e.g., diagonal band, medial septal, nucleus basalis) and the pontine-mesencephalic nuclei, respectively. Despite the fundamental role of cholinergic signaling in the CNS and the long standing knowledge of the organization of cholinergic circuitry, remarkably little is known about precisely how ACh release modulates cortical and subcortical neural activity and the behaviors these circuits subserve. Growing interest in cholinergic signaling in the CNS focuses on the mechanism(s) of action by which endogenously released ACh regulates cognitive functions, acting as a neuromodulator and/or as a direct transmitter via nicotinic and muscarinic receptors. The development of optogenetic techniques has provided a valuable toolbox with which we can address these questions, as it allows the selective manipulation of the excitability of cholinergic inputs to the diverse array of cholinergic target fields within cortical and subcortical domains. Here, we review recent papers that use the light-sensitive opsins in the cholinergic system to elucidate the role of ACh in circuits related to attention and emotionally salient behaviors. In particular, we highlight recent optogenetic studies which have tried to disentangle the precise role of ACh in the modulation of cortical-, hippocampal- and striatal-dependent functions.
PMCID: PMC4209819  PMID: 25386136
acetylcholine; optogenetics; nicotinic receptors; limbic circuitries; attention
5.  Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction 
Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction.
PMCID: PMC4299443  PMID: 25653591
addiction; drugs of abuse; synaptic plasticity; glutamate; dopamine; ventral tegmental area; nucleus accumbens; prefrontal cortex
6.  Cholinergic modulation of the medial prefrontal cortex: the role of nicotinic receptors in attention and regulation of neuronal activity 
Acetylcholine (ACh) release in the medial prefrontal cortex (mPFC) is crucial for normal cognitive performance. Despite the fact that many have studied how ACh affects neuronal processing in the mPFC and thereby influences attention behavior, there is still a lot unknown about how this occurs. Here we will review the evidence that cholinergic modulation of the mPFC plays a role in attention and we will summarize the current knowledge about the role between ACh receptors (AChRs) and behavior and how ACh receptor activation changes processing in the cortical microcircuitry. Recent evidence implicates fast phasic release of ACh in cue detection and attention. This review will focus mainly on the fast ionotropic nicotinic receptors and less on the metabotropic muscarinic receptors. Finally, we will review limitations of the existing studies and address how innovative technologies might push the field forward in order to gain understanding into the relation between ACh, neuronal activity and behavior.
PMCID: PMC3949318  PMID: 24653678
acetylcholine; nicotinic receptors; medial prefrontal cortex; attention; neurophysiology
7.  Nicotine Exposure during Adolescence Leads to Short- and Long-Term Changes in Spike Timing-Dependent Plasticity in Rat Prefrontal Cortex 
Adolescence is a critical period of brain development during which maturation of areas involved in cognitive functioning, such as the medial prefrontal cortex (mPFC), is still ongoing. Tobacco smoking during this age can compromise the normal course of prefrontal development and lead to cognitive impairments in later life. Recently, we reported that nicotine exposure during adolescence results in a short-term increase and lasting reduction in synaptic mGluR2 levels in the rat mPFC, causing attention deficits during adulthood. It is unknown how changed synaptic mGluR2 levels after adolescent nicotine exposure affect the ability of mPFC synapses to undergo long-term synaptic plasticity. Here, we addressed this question. To model nicotine exposure, adolescent (P34–P43) or adult (P60–P69) rats were treated with nicotine injections three times per day for 10 d. We found that, both during acute activation of nicotinic receptors in the adolescent mPFC as well as immediately following nicotine treatment during adolescence, long-term plasticity in response to timed presynaptic and postsynaptic activity (tLTP) was strongly reduced. In contrast, in the mPFC of adult rats 5 weeks after they received nicotine treatment during adolescence, but not during adulthood, tLTP was increased. Short-and long-term adaptation of mPFC synaptic plasticity after adolescent nicotine exposure could be explained by changed mGluR2 signaling. Blocking mGluR2s augmented tLTP, whereas activating mGluR2s reduced tLTP. Our findings suggest neuronal mechanisms by which exposure to nicotine during adolescence alters the rules for spike timing-dependent plasticity in prefrontal networks that may explain the observed deficits in cognitive performance in later life.
PMCID: PMC3552309  PMID: 22855798
8.  Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood 
The majority of adolescents report to have smoked a cigarette at least once. Adolescence is a critical period of brain development during which maturation of areas involved in cognitive functioning, such as the medial prefrontal cortex (mPFC), is still ongoing. Tobacco smoking during this age may compromise the normal course of prefrontal development and lead to cognitive impairments in later life. In addition, adolescent smokers suffer from attention deficits, which progress with the years of smoking. Recent studies in rodents reveal the molecular changes induced by adolescent nicotine exposure that alter the functioning of synapses in the PFC and underlie the lasting effects on cognitive function. In particular, the expression and function of metabotropic glutamate receptors (mGluRs) are changed and this has an impact on short- and long-term plasticity of glutamatergic synapses in the PFC and ultimately on the attention performance. Here, we review and discuss these recent findings.
PMCID: PMC3410598  PMID: 22876231
adolescence; nicotine; prefrontal cortex; STDP; mGluR; nAChR; cognitive behavior
9.  Presynaptic Ionotropic Receptors Controlling and Modulating the Rules for Spike Timing-Dependent Plasticity 
Neural Plasticity  2011;2011:870763.
Throughout life, activity-dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience. In line with predictions made by Hebb, synapse strength can be modified depending on the millisecond timing of action potential firing (STDP). The sign of synaptic plasticity depends on the spike order of presynaptic and postsynaptic neurons. Ionotropic neurotransmitter receptors, such as NMDA receptors and nicotinic acetylcholine receptors, are intimately involved in setting the rules for synaptic strengthening and weakening. In addition, timing rules for STDP within synapses are not fixed. They can be altered by activation of ionotropic receptors located at, or close to, synapses. Here, we will highlight studies that uncovered how network actions control and modulate timing rules for STDP by activating presynaptic ionotropic receptors. Furthermore, we will discuss how interaction between different types of ionotropic receptors may create “timing” windows during which particular timing rules lead to synaptic changes.
PMCID: PMC3173883  PMID: 21941664
10.  Layer-specific cholinergic control of human and mouse cortical synaptic plasticity 
Nature Communications  2016;7:12826.
Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans.
Nicotinic acetylcholine receptors (nAChRs) are differentially expressed across cortical layers, yet it is unclear whether they show layer-specific effects on synaptic plasticity in the prefrontal cortex. Here, the authors compare nAChRs across L6 and L2/3 in human and mouse cortex and find they mediate opposite effects on synaptic plasticity.
PMCID: PMC5025530  PMID: 27604129
11.  GABAergic Synapse Properties May Explain Genetic Variation in Hippocampal Network Oscillations in Mice 
Cognitive ability and the properties of brain oscillation are highly heritable in humans. Genetic variation underlying oscillatory activity might give rise to differences in cognition and behavior. How genetic diversity translates into altered properties of oscillations and synchronization of neuronal activity is unknown. To address this issue, we investigated cellular and synaptic mechanisms of hippocampal fast network oscillations in eight genetically distinct inbred mouse strains. The frequency of carbachol-induced oscillations differed substantially between mouse strains. Since GABAergic inhibition sets oscillation frequency, we studied the properties of inhibitory synaptic inputs (IPSCs) received by CA3 and CA1 pyramidal cells of three mouse strains that showed the highest, lowest and intermediate frequencies of oscillations. In CA3 pyramidal cells, the frequency of rhythmic IPSC input showed the same strain differences as the frequency of field oscillations. Furthermore, IPSC decay times in both CA1 and CA3 pyramidal cells were faster in mouse strains with higher oscillation frequencies than in mouse strains with lower oscillation frequency, suggesting that differences in GABAA-receptor subunit composition exist between these strains. Indeed, gene expression of GABAA-receptor β2 (Gabrb2) and β3 (Gabrb2) subunits was higher in mouse strains with faster decay kinetics compared with mouse strains with slower decay kinetics. Hippocampal pyramidal neurons in mouse strains with higher oscillation frequencies and faster decay kinetics fired action potential at higher frequencies. These data indicate that differences in genetic background may result in different GABAA-receptor subunit expression, which affects the rhythm of pyramidal neuron firing and fast network activity through GABA synapse kinetics.
PMCID: PMC2901093  PMID: 21082021
fast network oscillations; GABA synapses; heritability; hippocampus; GABA receptor subunits; C57; Balbc; NOD
12.  Human Synapses Show a Wide Temporal Window for Spike-Timing-Dependent Plasticity 
Throughout our lifetime, activity-dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience. Synapses can bi-directionally alter strength and the magnitude and sign depend on the millisecond timing of presynaptic and postsynaptic action potential firing. Recent findings on laboratory animals have shown that neurons can show a variety of temporal windows for spike-timing-dependent plasticity (STDP). It is unknown what synaptic learning rules exist in human synapses and whether similar temporal windows for STDP at synapses hold true for the human brain. Here, we directly tested in human slices cut from hippocampal tissue removed for surgical treatment of deeper brain structures in drug-resistant epilepsy patients, whether adult human synapses can change strength in response to millisecond timing of pre- and postsynaptic firing. We find that adult human hippocampal synapses can alter synapse strength in response to timed pre- and postsynaptic activity. In contrast to rodent hippocampal synapses, the sign of plasticity does not sharply switch around 0-ms timing. Instead, both positive timing intervals, in which presynaptic firing preceded the postsynaptic action potential, and negative timing intervals, in which postsynaptic firing preceded presynaptic activity down to −80 ms, increase synapse strength (tLTP). Negative timing intervals between −80 to −130 ms induce a lasting reduction of synapse strength (tLTD). Thus, similar to rodent synapses, adult human synapses can show spike-timing-dependent changes in strength. The timing rules of STDP in human hippocampus, however, seem to differ from rodent hippocampus, and suggest a less strict interpretation of Hebb's predictions.
PMCID: PMC3059666  PMID: 21423498
human; synapse; hippocampus; neocortex; synaptic plasticity; spike-timing-dependent plasticity; Hebbian plasticity
13.  Resting-State Subjective Experience and EEG Biomarkers Are Associated with Sleep-Onset Latency 
Difficulties initiating sleep are common in several disorders, including insomnia and attention deficit hyperactivity disorder. These disorders are prevalent, bearing significant societal and financial costs which require the consideration of new treatment strategies and a better understanding of the physiological and cognitive processes surrounding the time of preparing for sleep or falling asleep. Here, we search for neuro-cognitive associations in the resting state and examine their relevance for predicting sleep-onset latency using multi-level mixed models. Multiple EEG recordings were obtained from healthy male participants (N = 13) during a series of 5 min eyes-closed resting-state trials (in total, n = 223) followed by a period–varying in length up to 30 min–that either allowed subjects to transition into sleep (“sleep trials,” nsleep = 144) or was ended while they were still awake (“wake trials,” nwake = 79). After both eyes-closed rest, sleep and wake trials, subjective experience was assessed using the Amsterdam Resting-State Questionnaire (ARSQ). Our data revealed multiple associations between eyes-closed rest alpha and theta oscillations and ARSQ-dimensions Discontinuity of Mind, Self, Theory of Mind, Planning, and Sleepiness. The sleep trials showed that the transition toward the first sleep stage exclusively affected subjective experiences related to Theory of Mind, Planning, and Sleepiness. Importantly, sleep-onset latency was negatively associated both with eyes-closed rest ratings on the ARSQ dimension of Sleepiness and with the long-range temporal correlations of parietal theta oscillations derived by detrended fluctuation analysis (DFA). These results could be relevant to the development of personalized tools that help evaluate the success of falling asleep based on measures of resting-state cognition and EEG biomarkers.
PMCID: PMC4828461  PMID: 27148107
Amsterdam Resting-State Questionnaire (ARSQ); consciousness; mind wandering; sleep; multilevel modeling
14.  Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity 
Nature Communications  2016;7:10682.
Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission.
Auxiliary AMPA receptor subunits can affect gating and surface mobility. Here the authors show that Shisa6 traps AMPA receptors at postsynaptic sites via PSD-95, and keeps them in an activated state in the presence of glutamate, preventing full desensitization and consequently synaptic depression.
PMCID: PMC4778035  PMID: 26931375
15.  Resting-State fMRI Functional Connectivity Is Associated with Sleepiness, Imagery, and Discontinuity of Mind 
PLoS ONE  2015;10(11):e0142014.
Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to investigate the functional architecture of the healthy human brain and how it is affected by learning, lifelong development, brain disorders or pharmacological intervention. Non-sensory experiences are prevalent during rest and must arise from ongoing brain activity, yet little is known about this relationship. Here, we used two runs of rs-fMRI both immediately followed by the Amsterdam Resting-State Questionnaire (ARSQ) to investigate the relationship between functional connectivity within ten large-scale functional brain networks and ten dimensions of thoughts and feelings experienced during the scan in 106 healthy participants. We identified 11 positive associations between brain-network functional connectivity and ARSQ dimensions. ‘Sleepiness’ exhibited significant associations with functional connectivity within Visual, Sensorimotor and Default Mode networks. Similar associations were observed for ‘Visual Thought’ and ‘Discontinuity of Mind’, which may relate to variation in imagery and thought control mediated by arousal fluctuations. Our findings show that self-reports of thoughts and feelings experienced during a rs-fMRI scan help understand the functional significance of variations in functional connectivity, which should be of special relevance to clinical studies.
PMCID: PMC4634926  PMID: 26540239
16.  Beyond Columnar Organization: Cell Type- and Target Layer-Specific Principles of Horizontal Axon Projection Patterns in Rat Vibrissal Cortex 
Cerebral Cortex (New York, NY)  2015;25(11):4450-4468.
Vertical thalamocortical afferents give rise to the elementary functional units of sensory cortex, cortical columns. Principles that underlie communication between columns remain however unknown. Here we unravel these by reconstructing in vivo-labeled neurons from all excitatory cell types in the vibrissal part of rat primary somatosensory cortex (vS1). Integrating the morphologies into an exact 3D model of vS1 revealed that the majority of intracortical (IC) axons project far beyond the borders of the principal column. We defined the corresponding innervation volume as the IC-unit. Deconstructing this structural cortical unit into its cell type-specific components, we found asymmetric projections that innervate columns of either the same whisker row or arc, and which subdivide vS1 into 2 orthogonal [supra-]granular and infragranular strata. We show that such organization could be most effective for encoding multi whisker inputs. Communication between columns is thus organized by multiple highly specific horizontal projection patterns, rendering IC-units as the primary structural entities for processing complex sensory stimuli.
PMCID: PMC4816792  PMID: 25838038
barrel cortex; excitatory; intracortical unit; multiwhisker; transcolumnar
17.  H-Channels Affect Frequency, Power and Amplitude Fluctuations of Neuronal Network Oscillations 
Oscillations in network activity are ubiquitous in the brain and are involved in diverse cognitive functions. Oscillation characteristics, such as power, frequency, and temporal structure, depend on both network connectivity and intrinsic cellular properties, such as ion channel composition. An important class of channels, with key roles in regulating cell excitability, are h-channels. The h-current (Ih) is a slow, hyperpolarization-activated, depolarizing current that contributes to neuronal resonance and membrane potential. The impact of Ih on network oscillations, however, remains poorly understood. To elucidate the network effects of Ih, we used a computational model of a generic oscillatory neuronal network consisting of inhibitory and excitatory cells that were externally driven by excitatory action potentials and sustained depolarizing currents. We found that Ih increased the oscillation frequency and, in combination with external action potentials, representing input from areas outside the network, strongly decreased the synchrony of firing. As a consequence, the oscillation power and the duration of episodes during which the network exhibited high-amplitude oscillations were greatly reduced in the presence of Ih. Our results suggest that modulation of Ih or impaired expression of h-channels, as observed in epilepsy, could, by affecting oscillation dynamics, markedly alter network-level activity and potentially influence oscillation-dependent cognitive processes such as learning, memory and attention.
PMCID: PMC4652018  PMID: 26635594
h-channels; oscillations; synchrony; amplitude fluctuations; computational model
18.  Short- and Long-Term Consequences of Nicotine Exposure during Adolescence for Prefrontal Cortex Neuronal Network Function 
More than 70% of adolescents report to have smoked a cigarette at least once. At the adolescent stage the brain has not completed its maturation. The prefrontal cortex (PFC), the brain area responsible for executive functions and attention performance, is one of the last brain areas to mature and is still developing during adolescence. Smoking during adolescence increases the risk of developing psychiatric disorders and cognitive impairment in later life. In addition, adolescent smokers suffer from attention deficits, which aggravate with the years of smoking. Recent studies in rodents reveal the molecular changes induced by adolescent nicotine exposure that alter the functioning of synapses in the PFC and that underlie the lasting effects on cognitive function. Here we provide an overview of these recent findings.
Nicotine exposure during adolescence alters acetylcholine and glutamate receptor signaling in the prefrontal cortex, one of the last brain areas to mature. This may help explain altered cognitive function and attention performance in adolescents who smoke.
PMCID: PMC3543069  PMID: 22983224
19.  High Bandwidth Synaptic Communication and Frequency Tracking in Human Neocortex 
PLoS Biology  2014;12(11):e1002007.
Because of fast recovery from synaptic depression and fast-initiated action potentials, neuronal information transfer can have a substantially higher bandwidth in human neocortical circuits than in those of rodents.
Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits.
Author Summary
Our ability to think, memorize information, and act appropriately depends on circuits of connected neurons in the brain. In these circuits, neurons pass information to each other using electric pulses (action potentials) that cause the release of chemical neurotransmitters, which alter the membrane electric potential of receiving neurons. Based on the inputs neurons receive, they decide whether to transmit action potentials to other neurons in the circuit to pass on information. During sequences of repeated information transfer, synaptic connections between two neurons temporarily become weaker by synaptic depression. Our knowledge of neuronal information transfer is based on rodent neurons. The properties of synaptic information transfer and synaptic depression in humans are not known. Here, we show that adult human neurons can transfer information with up to ten times higher rates than mouse neurons, because of a three to four times faster recovery from depression. Furthermore, we found that human neurons can respond faster to synaptic inputs, owing to faster initiation of action potentials. Human neurons can thereby reliably encode high input frequencies in their output. Thus, neuronal information transfer can have a substantially higher bandwidth in human neocortical circuits than in rodent brains.
PMCID: PMC4244038  PMID: 25422947
20.  Inter-Network Interactions: Impact of Connections between Oscillatory Neuronal Networks on Oscillation Frequency and Pattern 
PLoS ONE  2014;9(7):e100899.
Oscillations in electrical activity are a characteristic feature of many brain networks and display a wide variety of temporal patterns. A network may express a single oscillation frequency, alternate between two or more distinct frequencies, or continually express multiple frequencies. In addition, oscillation amplitude may fluctuate over time. The origin of this complex repertoire of activity remains unclear. Different cortical layers often produce distinct oscillation frequencies. To investigate whether interactions between different networks could contribute to the variety of oscillation patterns, we created two model networks, one generating on its own a relatively slow frequency (20 Hz; slow network) and one generating a fast frequency (32 Hz; fast network). Taking either the slow or the fast network as source network projecting connections to the other, or target, network, we systematically investigated how type and strength of inter-network connections affected target network activity. For high inter-network connection strengths, we found that the slow network was more effective at completely imposing its rhythm on the fast network than the other way around. The strongest entrainment occurred when excitatory cells of the slow network projected to excitatory or inhibitory cells of the fast network. The fast network most strongly imposed its rhythm on the slow network when its excitatory cells projected to excitatory cells of the slow network. Interestingly, for lower inter-network connection strengths, multiple frequencies coexisted in the target network. Just as observed in rat prefrontal cortex, the target network could express multiple frequencies at the same time, alternate between two distinct oscillation frequencies, or express a single frequency with alternating episodes of high and low amplitude. Together, our results suggest that input from other oscillating networks may markedly alter a network's frequency spectrum and may partly be responsible for the rich repertoire of temporal oscillation patterns observed in the brain.
PMCID: PMC4090128  PMID: 25007325
21.  Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease 
Alzheimer’s disease is caused by increased production or reduced clearance of amyloid-β, which results in the formation amyloid-β plaques and triggers a cascade of downstream events leading to progressive neurodegeneration. The earliest clinical symptoms of Alzheimer’s disease, i.e., memory loss, are however poorly understood from a molecular and cellular perspective. Here we used APPswe/PS1dE9 (APP/PS1) transgenic mice to study the early pre-pathological effects of increased amyloid-β levels on hippocampal synaptic plasticity and memory. Using an unbiased proteomics approach we show that the early increase in amyloid-β levels in APP/PS1 mice at three months of age coincides with a robust and significant upregulation of several protein components of the extracellular matrix in hippocampal synaptosome preparations. This increase in extracellular matrix levels occurred well before the onset of plaque formation and was paralleled by impairments in hippocampal long-term potentiation and contextual memory. Direct injection into the hippocampus of the extracellular matrix inactivating enzyme chondroitinase ABC restored both long-term potentiation and contextual memory performance. These findings indicate an important role for the extracellular matrix in causing early memory loss in Alzheimer’s disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0076-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4149201  PMID: 24974208
Alzheimer’s disease; Hippocampus; Memory; Plasticity; Extracellular matrix; Perineuronal net
22.  Ventromedial Prefrontal Cortex Pyramidal Cells Have a Temporal Dynamic Role in Recall and Extinction of Cocaine-Associated Memory 
The Journal of Neuroscience  2013;33(46):18225-18233.
In addicts, associative memories related to the rewarding effects of drugs of abuse can evoke powerful craving and drug seeking urges, but effective treatment to suppress these memories is not available. Detailed insight into the neural circuitry that mediates expression of drug-associated memory is therefore of crucial importance. Substantial evidence from rodent models of addictive behavior points to the involvement of the ventromedial prefrontal cortex (vmPFC) in conditioned drug seeking, but specific knowledge of the temporal role of vmPFC pyramidal cells is lacking. To this end, we used an optogenetics approach to probe the involvement of vmPFC pyramidal cells in expression of a recent and remote conditioned cocaine memory. In mice, we expressed Channelrhodopsin-2 (ChR2) or Halorhodopsin (eNpHR3.0) in pyramidal cells of the vmPFC and studied the effect of activation or inhibition of these cells during expression of a cocaine-contextual memory on days 1–2 (recent) and ∼3 weeks (remote) after conditioning. Whereas optical activation of pyramidal cells facilitated extinction of remote memory, without affecting recent memory, inhibition of pyramidal cells acutely impaired recall of recent cocaine memory, without affecting recall of remote memory. In addition, we found that silencing pyramidal cells blocked extinction learning at the remote memory time-point. We provide causal evidence of a critical time-dependent switch in the contribution of vmPFC pyramidal cells to recall and extinction of cocaine-associated memory, indicating that the circuitry that controls expression of cocaine memories reorganizes over time.
PMCID: PMC3828471  PMID: 24227731
23.  Optimal lens design and use in laser-scanning microscopy 
Biomedical Optics Express  2014;5(5):1588-1609.
In laser-scanning microscopy often an off-the-shelf achromatic doublet is used as a scan lens which can reduce the available diffraction-limited field-of-view (FOV) by a factor of 3 and introduce chromatic aberrations that are scan angle dependent. Here we present several simple lens designs of superior quality that fully make use of high-NA low-magnification objectives, offering diffraction-limited imaging over a large FOV and wavelength range. We constructed a two-photon laser-scanning microscope with optimized custom lenses which had a near diffraction limit point-spread-function (PSF) with less than 3.6% variation over a 400 µm FOV and less than 0.5 µm lateral color between 750 and 1050 nm.
PMCID: PMC4026907  PMID: 24877017
(180.0180) Microscopy; (180.1790) Confocal microscopy; (180.4315) Nonlinear microscopy; (220.3620) Lens system design; (220.3630) Lenses
24.  The ARSQ 2.0 reveals age and personality effects on mind-wandering experiences 
The human brain frequently generates thoughts and feelings detached from environmental demands. Investigating the rich repertoire of these mind-wandering experiences is challenging, as it depends on introspection and mapping its content requires an unknown number of dimensions. We recently developed a retrospective self-report questionnaire—the Amsterdam Resting-State Questionnaire (ARSQ)—which quantifies mind wandering along seven dimensions: “Discontinuity of Mind,” “Theory of Mind,” “Self,” “Planning,” “Sleepiness,” “Comfort,” and “Somatic Awareness.” Here, we show using confirmatory factor analysis that the ARSQ can be simplified by standardizing the number of items per factor and extending it to a 10-dimensional model, adding “Health Concern,” “Visual Thought,” and “Verbal Thought.” We will refer to this extended ARSQ as the “ARSQ 2.0.” Testing for effects of age and gender revealed no main effect for gender, yet a moderate and significant negative effect for age on the dimensions of “Self,” “Planning,” and “Visual Thought.” Interestingly, we observed stable and significant test-retest correlations across measurement intervals of 3–32 months except for “Sleepiness” and “Health Concern.” To investigate whether this stability could be related to personality traits, we correlated ARSQ scores to proxy measures of Cloninger's Temperament and Character Inventory, revealing multiple significant associations for the trait “Self-Directedness.” Other traits correlated to specific ARSQ dimensions, e.g., a negative association between “Harm Avoidance” and “Comfort.” Together, our results suggest that the ARSQ 2.0 is a promising instrument for quantitative studies on mind wandering and its relation to other psychological or physiological phenomena.
PMCID: PMC3982068  PMID: 24772097
Amsterdam Resting-State Questionnaire (ARSQ); consciousness; mind wandering; personality traits; test-retest reliability
25.  Competitive Dynamics during Resource-Driven Neurite Outgrowth 
PLoS ONE  2014;9(2):e86741.
Neurons form networks by growing out neurites that synaptically connect to other neurons. During this process, neurites develop complex branched trees. Interestingly, the outgrowth of neurite branches is often accompanied by the simultaneous withdrawal of other branches belonging to the same tree. This apparent competitive outgrowth between branches of the same neuron is relevant for the formation of synaptic connectivity, but the underlying mechanisms are unknown. An essential component of neurites is the cytoskeleton of microtubules, long polymers of tubulin dimers running throughout the entire neurite. To investigate whether competition between neurites can emerge from the dynamics of a resource such as tubulin, we developed a multi-compartmental model of neurite growth. In the model, tubulin is produced in the soma and transported by diffusion and active transport to the growth cones at the tip of the neurites, where it is assembled into microtubules to elongate the neurite. Just as in experimental studies, we find that the outgrowth of a neurite branch can lead to the simultaneous retraction of its neighboring branches. We show that these competitive interactions occur in simple neurite morphologies as well as in complex neurite arborizations and that in developing neurons competition for a growth resource such as tubulin can account for the differential outgrowth of neurite branches. The model predicts that competition between neurite branches decreases with path distance between growth cones, increases with path distance from growth cone to soma, and decreases with a higher rate of active transport. Together, our results suggest that competition between outgrowing neurites can already emerge from relatively simple and basic dynamics of a growth resource. Our findings point to the need to test the model predictions and to determine, by monitoring tubulin concentrations in outgrowing neurons, whether tubulin is the resource for which neurites compete.
PMCID: PMC3911915  PMID: 24498280

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