Huibert Mansvelder - Academia.edu (original) (raw)

Papers by Huibert Mansvelder

Individual cortical layers have distinct roles in information processing. All layers receive chol... more 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.

Journal of Neuroscience, 2012

Criticality has gained widespread interest in neuroscience as an attractive framework for underst... more Criticality has gained widespread interest in neuroscience as an attractive framework for understanding the character and functional implications of variability in brain activity. The metastability of critical systems maximizes their dynamic range, storage capacity, and computational power. Power-law scaling-a hallmark of criticality-has been observed on different levels, e.g., in the distribution of neuronal avalanches in vitro and in vivo, but also in the decay of temporal correlations in behavioral performance and ongoing oscillations in humans. An unresolved issue is whether power-law scaling on different organizational levels in the brain-and possibly in other hierarchically organized systems-can be related. Here, we show that critical-state dynamics of avalanches and oscillations jointly emerge in a neuronal network model when excitation and inhibition is balanced. The oscillatory activity of the model was qualitatively similar to what is typically observed in recordings of human resting-state MEG. We propose that homeostatic plasticity mechanisms tune this balance in healthy brain networks, and that it is essential for critical behavior on multiple levels of neuronal organization with ensuing functional benefits. Based on our network model, we introduce a concept of multi-level criticality in which power-law scaling can emerge on multiple time scales in oscillating networks.

Tijdschrift voor Kindergeneeskunde, 2013

The EMBO journal, Jan 7, 2016

Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic ... more Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal-regulated kinase (ERK) that mediatesCB1R- andmGluR2/3-induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock-induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18-1. Mimicking constitutive phosphorylation of Munc18-1 results in a drastic decrease in synaptic transmission.ERK-mediated phosphorylation of Munc18-1 ultimately leads to degradation by the ubiquitin-proteasome system. Conversely, preventingERK-dependent Munc18-1 phosphorylation increases synaptic strength.CB1R- andmGluR2/3-induced synaptic inhibition and depolarization-induced suppression of excitation (DSE) are reduced uponERK/MEKpathway inhibition and further reduced whenERK-dependent Munc18-1 phosphorylation is blocke...

Science, 2011

More than one-third of all people are estimated to experience mild to severe cognitive impairment... more More than one-third of all people are estimated to experience mild to severe cognitive impairment as they age. Acetylcholine (ACh) levels in the brain diminish with aging, and nicotinic ACh receptor (nAChR) stimulation is known to enhance cognitive performance. The prefrontal cortex (PFC) is involved in a range of cognitive functions and is thought to mediate attentional focus. We found that mice carrying nAChR β2-subunit deletions have impaired attention performance. Efficient lentiviral vector-mediated reexpression of functional β2-subunit-containing nAChRs in PFC neurons of the prelimbic area (PrL) completely restored the attentional deficit but did not affect impulsive and motivational behavior. Our findings show that β2-subunit expression in the PrL PFC is sufficient for endogenous nAChR-mediated cholinergic regulation of attentional performance.

Nature communications, 2016

Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interact... more 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 p...

Plos One, 2010

It has previously been shown that deletion of chrna9, the gene encoding the alpha9 nicotinic acet... more It has previously been shown that deletion of chrna9, the gene encoding the alpha9 nicotinic acetylcholine receptor (nAChR) subunit, results in abnormal synaptic terminal structure. Additionally, all nAChR-mediated cochlear activity is lost, as characterized by a failure of the descending efferent system to suppress cochlear responses to sound. In an effort to characterize the molecular mechanisms underlying the structural and functional consequences following loss of alpha9 subunit expression, we performed whole-transcriptome gene expression analyses on cochleae of wild type and alpha9 knockout (alpha9(-/-)) mice during postnatal days spanning critical periods of synapse formation and maturation. Data revealed that loss of alpha9 receptor subunit expression leads to an up-regulation of genes involved in synaptic transmission and ion channel activity. Unexpectedly, loss of alpha9 receptor subunit expression also resulted in an increased expression of genes encoding GABA receptor subunits and the GABA synthetic enzyme, glutamic acid decarboxylase. These data suggest the existence of a previously unrecognized association between the nicotinic cholinergic and GABAergic systems in the cochlea. Computational analyses have highlighted differential expression of several gene sets upon loss of nicotinic cholinergic activity in the cochlea. Time-series analysis of whole transcriptome patterns, represented as self-organizing maps, revealed a disparate pattern of gene expression between alpha9(-/-) and wild type cochleae at the onset of hearing (P13), with knockout samples resembling immature postnatal ages. We have taken a systems biology approach to provide insight into molecular programs influenced by the loss of nicotinic receptor-based cholinergic activity in the cochlea and to identify candidate genes that may be involved in nicotinic cholinergic synapse formation, stabilization or function within the inner ear. Additionally, our data indicate a change in the GABAergic system upon loss of alpha9 nicotinic receptor subunit within the cochlea.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Dopamine and the neuropeptides Ala-Pro-Gly-Trp-NH 2 (APG-Wamide or APGWa) and Phe-Met-Arg-Phe-NH ... more Dopamine and the neuropeptides Ala-Pro-Gly-Trp-NH 2 (APG-Wamide or APGWa) and Phe-Met-Arg-Phe-NH 2 (FMRFamide or FMRFa) all activate an S-like potassium channel in the light green cells of the mollusc Lymnaea stagnalis, neuroendocrine cells that release insulin-related peptides. We studied the signaling pathways underlying the responses, the role of the G-protein ␤␥ subunit, and the interference by phosphorylation pathways. All responses are blocked by an inhibitor of arachidonic acid (AA) release, 4-bromophenacylbromide, and by inhibitors of lipoxygenases (nordihydroguaiaretic acid and AA-861) but not by indomethacin, a cyclooxygenase inhibitor. AA and phospholipase A 2 (PLA 2 ) induced currents with similar I-V characteristics and potassium selectivity as dopamine, APGWa, and FMRFa. PLA 2 occluded the response to FMRFa. We conclude that convergence of the actions of dopamine, APGWa, and FMRFa onto the S-like channel occurs at or upstream of the level of AA and that formation of lipoxygenase metabolites of AA is necessary to activate the channel. Injection of a synthetic peptide, which interferes with G-protein ␤␥ subunits, inhibited the agonist-induced potassium current. This suggests that ␤␥ subunits mediate the response, possibly by directly coupling to a phospholipase. Finally, the responses to dopamine, APGWa, and FMRFa were inhibited by activation of PKA and PKC, suggesting that the responses are counteracted by PKA-and PKC-dependent phosphorylation. The PLA 2 -activated potassium current was inhibited by 8-chlorophenylthio-cAMP but not by 12-O-tetradecanoylphorbol 13-acetate (TPA). However, TPA did inhibit the potassium current induced by irreversible activation of the G-protein using GTP-␥-S. Thus, it appears that PKA targets a site downstream of AA formation, e.g., the potassium channel, whereas PKC acts at the active G-protein or the phospholipase.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Melanotropic cells release predocked, large, dense-cored vesicles containing ␣-melanocyte stimula... more Melanotropic cells release predocked, large, dense-cored vesicles containing ␣-melanocyte stimulating hormone in response to calcium entry through voltage-gated calcium channels. Our first objective was to study the relationship between exocytosis, rapid endocytosis, and calcium entry evoked by short step depolarizations in the order of duration of single action potentials (APs). Exocytosis and rapid endocytosis were monitored by capacitance measurements. We show that short step depolarizations (40 msec) evoke the fast release of only ϳ3% of the predocked release-ready vesicle pool. Second, we asked what the distance is between voltage-gated calcium channels and predocked vesicles in these cells by modulating the intracellular buffer capacity. Exocytosis and rapid endocytosis were differentially affected by low concentrations of the calcium chelator EGTA. EGTA slightly attenuated exocytosis at 100 M relative to 50 M, but exocytosis was strongly depressed at 400 M, showing that calcium ions have to travel a large distance to stimulate exocytosis. Nevertheless, the efficacy of calcium ions to stimulate exocytosis was constant for pulse durations between 2 and 40 msec, indicating that in melanotropes, exocytosis is related linearly to the amount and duration of calcium entry during a single AP. Rapid endocytosis was already strongly depressed at 100 M EGTA, which shows that the process of endocytosis itself is calcium dependent in melanotropic cells. Furthermore, rapid endocytosis proceeded with a time constant of ϳ116 msec at 33°C, which is three times faster than at room temperature. There was a strong correlation between the amplitude of endocytosis and the amplitude of exocytosis immediately preceding endocytosis. Both this correlation and the fast time constant of endocytosis suggest that the exocytotic vesicle is retrieved rapidly.

PloS one, 2015

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to investigate the f... more 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 observ...

Journal of neurophysiology, Jan 13, 2016

Skeletal muscle force can be transmitted to the skeleton not only via its tendons of origin and i... more Skeletal muscle force can be transmitted to the skeleton not only via its tendons of origin and insertion, but also through connective tissues linking the muscle belly to surrounding structures. Through such epimuscular myofascial connections, length changes of a muscle may cause length changes within an adjacent muscle and, hence, affect muscle spindles. The aim of the present study was to investigate the effects of epimuscular myofascial forces on feedback from muscle spindles in triceps surae muscles of the rat. We hypothesized that, within an intact muscle compartment, muscle spindles not only signal length changes of the muscle they are located in, but can also sense length changes that occur as a result of changing the length of synergistic muscles. Action potentials from single afferents were measured intra-axonally in response to ramp-hold-release (RHR) stretches of an agonistic muscle at different lengths of its synergist, as well as in response to synergist RHRs. A decreas...

Cerebral Cortex, 2015

Hemanth Mohan and Matthijs B. Verhoog contributed equally to this work. ‡ Huibert D. Mansvelder a... more Hemanth Mohan and Matthijs B. Verhoog contributed equally to this work. ‡ Huibert D. Mansvelder and Christiaan P.J. de Kock share senior authorship.

Background: Insomnia is a prevalent disorder characterized by disturbances of the circadian rhyth... more Background: Insomnia is a prevalent disorder characterized by disturbances of the circadian rhythm, daytime sleepiness, and problems falling asleep. Different rhythm-improving measures have shown promise in normalizing sleep, e.g., early morning bright light and evening melatonin. EEG-neurofeedback is an alternative method that could prove valuable for helping people regulate their vigilance by finding appropriate cognitive strategies to enable them to fall asleep. Methods: Our feedback protocol targets the cortical arousal index (AI), which is based on the amplitude ratio between occipital-alpha and central-theta. Audio-feedback is coupled to the fluctuations of the AI over time, resulting in the sound fading away as the participant approaches sleep onset. We use two time scales to modulate the sound. The short time-scale is used by the subject to regulate the immediate arousal contingencies and is perceived as a change in the proximity of the sound. The long time-scale favours shi...

Biochemical Pharmacology, 2015

Developmental Neurobiology, 2015

Developing networks in the immature nervous system and in cellular cultures are characterized by ... more Developing networks in the immature nervous system and in cellular cultures are characterized by waves of synchronous activity in restricted clusters of cells. Synchronized activity in immature networks is proposed to regulate many different developmental processes, from neuron growth and cell migration, to the refinement of synapses, topographic maps, and the mature composition of ion channels. These emergent activity patterns are not present in all cells simultaneously within the network and more immature "silent" cells, potentially correlated with the presence of silent synapses, are prominent in different networks during early developmental periods. Many current network analyses for detection of synchronous cellular activity utilize activity-based pixel correlations to identify cellular-based regions of interest (ROIs) and coincident cell activity. However, using activity-based correlations, these methods first underestimate or ignore the inactive silent cells within the developing network and second, are difficult to apply within cell-dense regions commonly found in developing brain networks. In addition, previous methods may ignore ROIs within a network that shows transient activity patterns comprising both inactive and active periods. We developed analysis software to semi-automatically detect cells within developing neuronal networks that were imaged using calcium-sensitive reporter dyes. Using an iterative threshold, modulation of activity was tracked within individual cells across the network. The distribution pattern of both inactive and active, including synchronous cells, could be determined based on distance measures to neighboring cells and according to different anatomical layers. © 2015 Wiley Periodicals, Inc. Develop Neurobiol, 2015.

Communicative & integrative biology, 2011

Despite a long history of anatomical mapping of neuronal networks, we are only beginning to under... more Despite a long history of anatomical mapping of neuronal networks, we are only beginning to understand the detailed three-dimensional (3D) organization of the cortical micro-circuitry. This is in part due to the lack of complete reconstructions of individual cortical neurons. Morphological studies are either performed on incomplete cells in vitro, or when performed in vivo, lack the necessary cellular resolution. We recently reconstructed the in vivo axonal and dendritic morphology of two types of L(ayer) 5 neurons from vibrissal cortex. The 3D profiles of short-range as well as longrange projections indicate that L5 slender-tufted and L5 thick-tufted neurons represent very different building blocks of the cortical circuitry. In this addendum to Oberlaender et al. (PNAS 2011), we motivate our technical approach and the advancements this may give in reconstructing the cortical micro-circuitry.

Frontiers in synaptic neuroscience, 2010

Development of cognitive function requires the formation and refinement of synaptic networks of n... more Development of cognitive function requires the formation and refinement of synaptic networks of neurons in the brain. Morphological abnormalities of synaptic spines occur throughout the brain in a wide variety of syndromic and non-syndromic disorders of mental retardation (MR). In both neurons from human post-mortem tissue and mouse models of retardation, the changes observed in synaptic spine and dendritic morphology can be subtle, in the range of 10-20% alterations for spine protrusion length and density. Functionally, synapses in hippocampus and cortex show deficits in long-term potentiation (LTP) and long-term depression (LTD) in an array of neurodevelopmental disorders including Down's, Angelman, Fragile X and Rett syndrome. Recent studies have shown that in principle the machinery for synaptic plasticity is in place in these synapses, but that significant alterations in spike-timing-dependent plasticity (STDP) induction rules exist in cortical synaptic pathways of Fragile ...

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003

During the female reproductive cycle, hypothalamic oxytocin (OT) neurons undergo sharp changes in... more During the female reproductive cycle, hypothalamic oxytocin (OT) neurons undergo sharp changes in excitability. In lactating mammals, bursts of electrical activity of OT neurons result in the release of large amounts of OT in the bloodstream, which causes milk ejection. One hypothesis is that OT neurons regulate their own firing activity and that of nearby OT neurons by somatodendritic release of OT. In this study, we show that OT neuron activity strongly reduces inhibitory synaptic transmission to these neurons. This effect is blocked by antagonists of both adenosine and OT receptors and is mimicked by OT application. Inhibition of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex formation by tetanus toxin completely blocked the stimulation-induced reduction in inhibitory input, as did the calcium chelator BAPTA. During lactation, the readily releasable pool of secretory vesicles in OT cell bodies was doubled, and calcium currents were upregulated. This...

Cold Spring Harbor Perspectives in Medicine, 2012

More than 70% of adolescents report to have smoked a cigarette at least once. At the adolescent s... more 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.

Individual cortical layers have distinct roles in information processing. All layers receive chol... more 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.

Journal of Neuroscience, 2012

Criticality has gained widespread interest in neuroscience as an attractive framework for underst... more Criticality has gained widespread interest in neuroscience as an attractive framework for understanding the character and functional implications of variability in brain activity. The metastability of critical systems maximizes their dynamic range, storage capacity, and computational power. Power-law scaling-a hallmark of criticality-has been observed on different levels, e.g., in the distribution of neuronal avalanches in vitro and in vivo, but also in the decay of temporal correlations in behavioral performance and ongoing oscillations in humans. An unresolved issue is whether power-law scaling on different organizational levels in the brain-and possibly in other hierarchically organized systems-can be related. Here, we show that critical-state dynamics of avalanches and oscillations jointly emerge in a neuronal network model when excitation and inhibition is balanced. The oscillatory activity of the model was qualitatively similar to what is typically observed in recordings of human resting-state MEG. We propose that homeostatic plasticity mechanisms tune this balance in healthy brain networks, and that it is essential for critical behavior on multiple levels of neuronal organization with ensuing functional benefits. Based on our network model, we introduce a concept of multi-level criticality in which power-law scaling can emerge on multiple time scales in oscillating networks.

Tijdschrift voor Kindergeneeskunde, 2013

The EMBO journal, Jan 7, 2016

Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic ... more Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal-regulated kinase (ERK) that mediatesCB1R- andmGluR2/3-induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock-induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18-1. Mimicking constitutive phosphorylation of Munc18-1 results in a drastic decrease in synaptic transmission.ERK-mediated phosphorylation of Munc18-1 ultimately leads to degradation by the ubiquitin-proteasome system. Conversely, preventingERK-dependent Munc18-1 phosphorylation increases synaptic strength.CB1R- andmGluR2/3-induced synaptic inhibition and depolarization-induced suppression of excitation (DSE) are reduced uponERK/MEKpathway inhibition and further reduced whenERK-dependent Munc18-1 phosphorylation is blocke...

Science, 2011

More than one-third of all people are estimated to experience mild to severe cognitive impairment... more More than one-third of all people are estimated to experience mild to severe cognitive impairment as they age. Acetylcholine (ACh) levels in the brain diminish with aging, and nicotinic ACh receptor (nAChR) stimulation is known to enhance cognitive performance. The prefrontal cortex (PFC) is involved in a range of cognitive functions and is thought to mediate attentional focus. We found that mice carrying nAChR β2-subunit deletions have impaired attention performance. Efficient lentiviral vector-mediated reexpression of functional β2-subunit-containing nAChRs in PFC neurons of the prelimbic area (PrL) completely restored the attentional deficit but did not affect impulsive and motivational behavior. Our findings show that β2-subunit expression in the PrL PFC is sufficient for endogenous nAChR-mediated cholinergic regulation of attentional performance.

Nature communications, 2016

Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interact... more 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 p...

Plos One, 2010

It has previously been shown that deletion of chrna9, the gene encoding the alpha9 nicotinic acet... more It has previously been shown that deletion of chrna9, the gene encoding the alpha9 nicotinic acetylcholine receptor (nAChR) subunit, results in abnormal synaptic terminal structure. Additionally, all nAChR-mediated cochlear activity is lost, as characterized by a failure of the descending efferent system to suppress cochlear responses to sound. In an effort to characterize the molecular mechanisms underlying the structural and functional consequences following loss of alpha9 subunit expression, we performed whole-transcriptome gene expression analyses on cochleae of wild type and alpha9 knockout (alpha9(-/-)) mice during postnatal days spanning critical periods of synapse formation and maturation. Data revealed that loss of alpha9 receptor subunit expression leads to an up-regulation of genes involved in synaptic transmission and ion channel activity. Unexpectedly, loss of alpha9 receptor subunit expression also resulted in an increased expression of genes encoding GABA receptor subunits and the GABA synthetic enzyme, glutamic acid decarboxylase. These data suggest the existence of a previously unrecognized association between the nicotinic cholinergic and GABAergic systems in the cochlea. Computational analyses have highlighted differential expression of several gene sets upon loss of nicotinic cholinergic activity in the cochlea. Time-series analysis of whole transcriptome patterns, represented as self-organizing maps, revealed a disparate pattern of gene expression between alpha9(-/-) and wild type cochleae at the onset of hearing (P13), with knockout samples resembling immature postnatal ages. We have taken a systems biology approach to provide insight into molecular programs influenced by the loss of nicotinic receptor-based cholinergic activity in the cochlea and to identify candidate genes that may be involved in nicotinic cholinergic synapse formation, stabilization or function within the inner ear. Additionally, our data indicate a change in the GABAergic system upon loss of alpha9 nicotinic receptor subunit within the cochlea.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Dopamine and the neuropeptides Ala-Pro-Gly-Trp-NH 2 (APG-Wamide or APGWa) and Phe-Met-Arg-Phe-NH ... more Dopamine and the neuropeptides Ala-Pro-Gly-Trp-NH 2 (APG-Wamide or APGWa) and Phe-Met-Arg-Phe-NH 2 (FMRFamide or FMRFa) all activate an S-like potassium channel in the light green cells of the mollusc Lymnaea stagnalis, neuroendocrine cells that release insulin-related peptides. We studied the signaling pathways underlying the responses, the role of the G-protein ␤␥ subunit, and the interference by phosphorylation pathways. All responses are blocked by an inhibitor of arachidonic acid (AA) release, 4-bromophenacylbromide, and by inhibitors of lipoxygenases (nordihydroguaiaretic acid and AA-861) but not by indomethacin, a cyclooxygenase inhibitor. AA and phospholipase A 2 (PLA 2 ) induced currents with similar I-V characteristics and potassium selectivity as dopamine, APGWa, and FMRFa. PLA 2 occluded the response to FMRFa. We conclude that convergence of the actions of dopamine, APGWa, and FMRFa onto the S-like channel occurs at or upstream of the level of AA and that formation of lipoxygenase metabolites of AA is necessary to activate the channel. Injection of a synthetic peptide, which interferes with G-protein ␤␥ subunits, inhibited the agonist-induced potassium current. This suggests that ␤␥ subunits mediate the response, possibly by directly coupling to a phospholipase. Finally, the responses to dopamine, APGWa, and FMRFa were inhibited by activation of PKA and PKC, suggesting that the responses are counteracted by PKA-and PKC-dependent phosphorylation. The PLA 2 -activated potassium current was inhibited by 8-chlorophenylthio-cAMP but not by 12-O-tetradecanoylphorbol 13-acetate (TPA). However, TPA did inhibit the potassium current induced by irreversible activation of the G-protein using GTP-␥-S. Thus, it appears that PKA targets a site downstream of AA formation, e.g., the potassium channel, whereas PKC acts at the active G-protein or the phospholipase.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Melanotropic cells release predocked, large, dense-cored vesicles containing ␣-melanocyte stimula... more Melanotropic cells release predocked, large, dense-cored vesicles containing ␣-melanocyte stimulating hormone in response to calcium entry through voltage-gated calcium channels. Our first objective was to study the relationship between exocytosis, rapid endocytosis, and calcium entry evoked by short step depolarizations in the order of duration of single action potentials (APs). Exocytosis and rapid endocytosis were monitored by capacitance measurements. We show that short step depolarizations (40 msec) evoke the fast release of only ϳ3% of the predocked release-ready vesicle pool. Second, we asked what the distance is between voltage-gated calcium channels and predocked vesicles in these cells by modulating the intracellular buffer capacity. Exocytosis and rapid endocytosis were differentially affected by low concentrations of the calcium chelator EGTA. EGTA slightly attenuated exocytosis at 100 M relative to 50 M, but exocytosis was strongly depressed at 400 M, showing that calcium ions have to travel a large distance to stimulate exocytosis. Nevertheless, the efficacy of calcium ions to stimulate exocytosis was constant for pulse durations between 2 and 40 msec, indicating that in melanotropes, exocytosis is related linearly to the amount and duration of calcium entry during a single AP. Rapid endocytosis was already strongly depressed at 100 M EGTA, which shows that the process of endocytosis itself is calcium dependent in melanotropic cells. Furthermore, rapid endocytosis proceeded with a time constant of ϳ116 msec at 33°C, which is three times faster than at room temperature. There was a strong correlation between the amplitude of endocytosis and the amplitude of exocytosis immediately preceding endocytosis. Both this correlation and the fast time constant of endocytosis suggest that the exocytotic vesicle is retrieved rapidly.

PloS one, 2015

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to investigate the f... more 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 observ...

Journal of neurophysiology, Jan 13, 2016

Skeletal muscle force can be transmitted to the skeleton not only via its tendons of origin and i... more Skeletal muscle force can be transmitted to the skeleton not only via its tendons of origin and insertion, but also through connective tissues linking the muscle belly to surrounding structures. Through such epimuscular myofascial connections, length changes of a muscle may cause length changes within an adjacent muscle and, hence, affect muscle spindles. The aim of the present study was to investigate the effects of epimuscular myofascial forces on feedback from muscle spindles in triceps surae muscles of the rat. We hypothesized that, within an intact muscle compartment, muscle spindles not only signal length changes of the muscle they are located in, but can also sense length changes that occur as a result of changing the length of synergistic muscles. Action potentials from single afferents were measured intra-axonally in response to ramp-hold-release (RHR) stretches of an agonistic muscle at different lengths of its synergist, as well as in response to synergist RHRs. A decreas...

Cerebral Cortex, 2015

Hemanth Mohan and Matthijs B. Verhoog contributed equally to this work. ‡ Huibert D. Mansvelder a... more Hemanth Mohan and Matthijs B. Verhoog contributed equally to this work. ‡ Huibert D. Mansvelder and Christiaan P.J. de Kock share senior authorship.

Background: Insomnia is a prevalent disorder characterized by disturbances of the circadian rhyth... more Background: Insomnia is a prevalent disorder characterized by disturbances of the circadian rhythm, daytime sleepiness, and problems falling asleep. Different rhythm-improving measures have shown promise in normalizing sleep, e.g., early morning bright light and evening melatonin. EEG-neurofeedback is an alternative method that could prove valuable for helping people regulate their vigilance by finding appropriate cognitive strategies to enable them to fall asleep. Methods: Our feedback protocol targets the cortical arousal index (AI), which is based on the amplitude ratio between occipital-alpha and central-theta. Audio-feedback is coupled to the fluctuations of the AI over time, resulting in the sound fading away as the participant approaches sleep onset. We use two time scales to modulate the sound. The short time-scale is used by the subject to regulate the immediate arousal contingencies and is perceived as a change in the proximity of the sound. The long time-scale favours shi...

Biochemical Pharmacology, 2015

Developmental Neurobiology, 2015

Developing networks in the immature nervous system and in cellular cultures are characterized by ... more Developing networks in the immature nervous system and in cellular cultures are characterized by waves of synchronous activity in restricted clusters of cells. Synchronized activity in immature networks is proposed to regulate many different developmental processes, from neuron growth and cell migration, to the refinement of synapses, topographic maps, and the mature composition of ion channels. These emergent activity patterns are not present in all cells simultaneously within the network and more immature "silent" cells, potentially correlated with the presence of silent synapses, are prominent in different networks during early developmental periods. Many current network analyses for detection of synchronous cellular activity utilize activity-based pixel correlations to identify cellular-based regions of interest (ROIs) and coincident cell activity. However, using activity-based correlations, these methods first underestimate or ignore the inactive silent cells within the developing network and second, are difficult to apply within cell-dense regions commonly found in developing brain networks. In addition, previous methods may ignore ROIs within a network that shows transient activity patterns comprising both inactive and active periods. We developed analysis software to semi-automatically detect cells within developing neuronal networks that were imaged using calcium-sensitive reporter dyes. Using an iterative threshold, modulation of activity was tracked within individual cells across the network. The distribution pattern of both inactive and active, including synchronous cells, could be determined based on distance measures to neighboring cells and according to different anatomical layers. © 2015 Wiley Periodicals, Inc. Develop Neurobiol, 2015.

Communicative & integrative biology, 2011

Despite a long history of anatomical mapping of neuronal networks, we are only beginning to under... more Despite a long history of anatomical mapping of neuronal networks, we are only beginning to understand the detailed three-dimensional (3D) organization of the cortical micro-circuitry. This is in part due to the lack of complete reconstructions of individual cortical neurons. Morphological studies are either performed on incomplete cells in vitro, or when performed in vivo, lack the necessary cellular resolution. We recently reconstructed the in vivo axonal and dendritic morphology of two types of L(ayer) 5 neurons from vibrissal cortex. The 3D profiles of short-range as well as longrange projections indicate that L5 slender-tufted and L5 thick-tufted neurons represent very different building blocks of the cortical circuitry. In this addendum to Oberlaender et al. (PNAS 2011), we motivate our technical approach and the advancements this may give in reconstructing the cortical micro-circuitry.

Frontiers in synaptic neuroscience, 2010

Development of cognitive function requires the formation and refinement of synaptic networks of n... more Development of cognitive function requires the formation and refinement of synaptic networks of neurons in the brain. Morphological abnormalities of synaptic spines occur throughout the brain in a wide variety of syndromic and non-syndromic disorders of mental retardation (MR). In both neurons from human post-mortem tissue and mouse models of retardation, the changes observed in synaptic spine and dendritic morphology can be subtle, in the range of 10-20% alterations for spine protrusion length and density. Functionally, synapses in hippocampus and cortex show deficits in long-term potentiation (LTP) and long-term depression (LTD) in an array of neurodevelopmental disorders including Down's, Angelman, Fragile X and Rett syndrome. Recent studies have shown that in principle the machinery for synaptic plasticity is in place in these synapses, but that significant alterations in spike-timing-dependent plasticity (STDP) induction rules exist in cortical synaptic pathways of Fragile ...

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003

During the female reproductive cycle, hypothalamic oxytocin (OT) neurons undergo sharp changes in... more During the female reproductive cycle, hypothalamic oxytocin (OT) neurons undergo sharp changes in excitability. In lactating mammals, bursts of electrical activity of OT neurons result in the release of large amounts of OT in the bloodstream, which causes milk ejection. One hypothesis is that OT neurons regulate their own firing activity and that of nearby OT neurons by somatodendritic release of OT. In this study, we show that OT neuron activity strongly reduces inhibitory synaptic transmission to these neurons. This effect is blocked by antagonists of both adenosine and OT receptors and is mimicked by OT application. Inhibition of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex formation by tetanus toxin completely blocked the stimulation-induced reduction in inhibitory input, as did the calcium chelator BAPTA. During lactation, the readily releasable pool of secretory vesicles in OT cell bodies was doubled, and calcium currents were upregulated. This...

Cold Spring Harbor Perspectives in Medicine, 2012

More than 70% of adolescents report to have smoked a cigarette at least once. At the adolescent s... more 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.

Neurons make synaptic connections at locations where axons and dendrites are sufficiently close i... more Neurons make synaptic connections at locations where axons and dendrites are sufficiently close in space. Typically the required proximity is based on the dimensions of dendritic spines and axonal boutons. Based on this principle one can search those locations in networks formed by reconstructed neurons or computer generated neurons. Candidate synapses are then located where axons and dendrites are within a given criterion distance from each other. Both experimentally reconstructed and model generated neurons are usually represented morphologically by piecewise-linear structures (line pieces or cylinders). Proximity tests are then performed on all pairs of line pieces from both axonal and dendritic branches. Applying just a test on the distance between line pieces may result in local clusters of synaptic sites when more than one pair of nearby line pieces from axonal and dendritic branches is sufficient close, and may introduce a dependency on the length scale of the individual line pieces. The present paper describes a new algorithm for defining locations of candidate synapses which is based on the crossing requirement of a line piece pair, while the length of the orthogonal distance between the line pieces is subjected to the distance criterion for testing 3D proximity.