rudyvdbrink/CitationDatabase huggingface dataset:
Impaired functional organization in the visual cortex of muscarinic receptor knock-out mice.
NeuroImage, 2014

Acetylcholine modulates maturation and neuronal activity through muscarinic and nicotinic receptors in the primary visual cortex. However, the specific contribution of different muscarinic receptor subtypes in these neuromodulatory mechanisms is not fully understood. The present study evaluates in vivo the functional organization and the properties of the visual cortex of different groups of muscarinic receptor knock-out (KO) mice. Optical imaging of intrinsic signals coupled to continuous and episodic visual stimulation paradigms was used. Retinotopic maps along elevation and azimuth were preserved among the different groups of mice. However, compared to their wild-type counterparts, the apparent visual field along elevation was larger in M2/M4-KO mice but smaller in M1-KO. There was a reduction in the estimated relative receptive field size of V1 neurons in M1/M3-KO and M1-KO mice. Spatial frequency and contrast selectivity of V1 neuronal populations were affected only in M1/M3-KO and M1-KO mice. Finally, the neuronal connectivity was altered by the absence of M2/M4 muscarinic receptors. All these effects suggest the distinct roles of different subtypes of muscarinic receptors in the intrinsic organization of V1 and a strong involvement of the muscarinic transmission in the detectability of visual stimuli.
Tissue-nonspecific alkaline phosphatase acts redundantly with PAP and NT5E to generate adenosine in the dorsal spinal cord.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

Prostatic acid phosphatase (PAP) and ecto-5'-nucleotidase (NT5E) hydrolyze extracellular AMP to adenosine in dorsal root ganglia (DRG) neurons and in the dorsal spinal cord. Previously, we found that adenosine production was reduced, but not eliminated, in Pap⁻/⁻/Nt5e⁻/⁻ double knock-out (dKO) mice, suggesting that a third AMP ectonucleotidase was present in these tissues. Here, we found that tissue-nonspecific alkaline phosphatase (TNAP, encoded by the Alpl gene) is expressed and functional in DRG neurons and spinal neurons. Using a cell-based assay, we found that TNAP rapidly hydrolyzed extracellular AMP and activated adenosine receptors. This activity was eliminated by MLS-0038949, a selective pharmacological inhibitor of TNAP. In addition, MLS-0038949 eliminated AMP hydrolysis in DRG and spinal lamina II of dKO mice. Using fast-scan-cyclic voltammetry, we found that adenosine was rapidly produced from AMP in spinal cord slices from dKO mice, but virtually no adenosine was produced in spinal cord slices from dKO mice treated with MLS-0038949. Last, we found that AMP inhibited excitatory neurotransmission via adenosine A1 receptor activation in spinal cord slices from wild-type, Pap⁻/⁻, Nt5e⁻/⁻, and dKO mice, but failed to inhibit neurotransmission in slices from dKO mice treated with MLS-0038949. These data suggest that triple elimination of TNAP, PAP, and NT5E is required to block AMP hydrolysis to adenosine in DRG neurons and dorsal spinal cord. Moreover, our data reveal that TNAP, PAP, and NT5E are the main AMP ectonucleotidases in primary somatosensory neurons and regulate physiology by metabolizing extracellular purine nucleotides.
Experimental Models of Glaucoma: A Powerful Translational Tool for the Future Development of New Therapies for Glaucoma in Humans-A Review of the Literature.
Medicina (Kaunas, Lithuania), 2019

Glaucoma is a common complex disease that leads to irreversible blindness worldwide. Even though preclinical studies showed that lowering intraocular pressure (IOP) could prevent retinal ganglion cells loss, clinical evidence suggests that lessening IOP does not prevent glaucoma progression in all patients. Glaucoma is also becoming more prevalent in the elderly population, showing that age is a recognized major risk factor. Indeed, recent findings suggest that age-related tissue alterations contribute to the development of glaucoma and have encouraged exploration for new treatment approaches. In this review, we provide information on the most frequently used experimental models of glaucoma and describe their advantages and limitations. Additionally, we describe diverse animal models of glaucoma that can be potentially used in translational medicine and aid an efficient shift to the clinic. Experimental animal models have helped to understand the mechanisms of formation and evacuation of aqueous humor, and the maintenance of homeostasis of intra-ocular pressure. However, the transfer of pre-clinical results obtained from animal studies into clinical trials may be difficult since the type of study does not only depend on the type of therapy to be performed, but also on a series of factors observed both in the experimental period and the period of transfer to clinical application. Conclusions: Knowing the exact characteristics of each glaucoma experimental model could help to diminish inconveniences related to the process of the translation of results into clinical application in humans.
Structural differences in the umbilical vein wall after full-term and pre-term delivery.
Anatomia, histologia, embryologia, 2009

With the exception of its most proximal segment, the human umbilical cord lacks innervation. It might be expected, therefore, that a paracrine effect through the direct contact between the smooth muscle cells and the endothelium may be particularly important in the control of the fetoplacental circulation. In this study, electron microscopy and immunohistochemistry were applied to examine umbilical veins immediately after full-term and pre-term delivery. The smooth muscle cells in the upper layer of the tunica media exhibited long, foot-like processes with c-kit immunoreactivity. In the umbilical vein of full-term neonates more than 50% of these cell processes display a normal ultrastructure and they were closely associated with the lamina elastica interna. Whereas in pre-term infants more than 60% of these cell processes exhibit signs of severe shrinkage and detachedness from the lamina elastica interna. At the same time, the high level of immunoreactivity of the endothelial cells as regards the proapoptotic gene product Bax in pre-term infants is indicative of an enhanced apoptotic process in these cells.
Symptoms of autism and ADHD: a Swedish twin study examining their overlap.
Journal of abnormal psychology, 2014

Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) show high comorbidity. The following questions were addressed regarding their specific symptoms: What is the factor structure of ASD and ADHD symptoms, to what degree do different symptom domains cluster together, to what extent are these domains caused by the same genetic and environmental influences, and what is the best model of their co-occurrence? A population-based twin cohort of over 17,000 9- and 12-year-olds were assessed using the Autism-Tics, AD/HD, and other Comorbidities parental interview inventory. Principal component analyses were conducted, and symptom domain clustering was assessed. Four multivariate twin models were compared. Factors split into three ASD (social impairments, communication impairments, and restricted repetitive behaviors and interests), and three ADHD (inattention, hyperactivity, and impulsivity) symptom domains. Some ASD-ADHD symptom domain combinations clustered together often, although others not at all. A two-factor common pathway model fit the data, suggesting that ASD and ADHD symptom domains tap into separate "ASD" and "ADHD" latent factors that showed high genetic overlap. All subdomains also showed significant specific genetic and environmental influences, reflecting the etiological heterogeneity both within and between ASD and ADHD. These findings support the conceptual distinction of ASD and ADHD, and demonstrate the considerable natural co-occurrence of particular ASD/ADHD symptom domains. The results imply that more children with 1 condition show features of the other condition than show complete comorbidity. Emphasis on symptom co-occurrence, rather than complete comorbidity between disorders, may help focus clinical approaches and advance molecular genetic research.
Hepatic rRNA transcription regulates high-fat-diet-induced obesity.
Cell reports, 2014

Ribosome biosynthesis is a major intracellular energy-consuming process. We previously identified a nucleolar factor, nucleomethylin (NML), which regulates intracellular energy consumption by limiting rRNA transcription. Here, we show that, in livers of obese mice, the recruitment of NML to rRNA gene loci is increased to repress rRNA transcription. To clarify the relationship between obesity and rRNA transcription, we generated NML-null (NML-KO) mice. NML-KO mice show elevated rRNA level, reduced ATP concentration, and reduced lipid accumulation in the liver. Furthermore, in high-fat-diet (HFD)-fed NML-KO mice, hepatic rRNA levels are not decreased. Both weight gain and fat accumulation in HFD-fed NML-KO mice are significantly lower than those in HFD-fed wild-type mice. These findings indicate that rRNA transcriptional activation promotes hepatic energy consumption, which alters hepatic lipid metabolism. Namely, hepatic rRNA transcriptional repression by HFD feeding is essential for energy storage.
Distinct mechanisms for size tuning in primate visual cortex.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011

Most neurons in primary visual cortex (V1) are selective for stimulus size, a property with important implications for salient feature detection. Size selectivity involves dynamic interactions between neuronal circuits that establish the classical (center) and extraclassical (surround) of a neuron's receptive field. Although much is known about the tuning properties and stimulus selectivity of the center and surround subunits, relatively little is known about how these subunits interact to achieve size selectivity. To address this question, we examined the temporal dynamics of size selectivity in two classes of pyramidal neurons at similar hierarchical processing stages in V1 of alert monkeys. These two classes were comprised of neurons in cortical layer 6 with identified projections to the lateral geniculate nucleus. While both neuronal groups displayed comparable levels of size selectivity, the temporal dynamics of their tuning differed significantly. We compared the size tuning profiles of each cell type with a series of sum-of-Gaussian models and discovered that the receptive fields of neurons with fast-conducting axons contained an excitatory center and a suppressive surround with similar onset timing. In contrast, neurons with slow-conducting axons used two center components-an early wide-field component and a delayed narrow-field component that increased activity-in addition to the surround component. The early, wide-field component represents a novel mechanism for cortical neurons to integrate contextual information. These results demonstrate that size tuning in cortical neurons is established via multiple unique mechanisms, dictated by the rich circuit architecture in which neurons are embedded.
Chronic spinal cord electrical stimulation protects against 6-hydroxydopamine lesions.
Scientific reports, 2014

Although L-dopa continues to be the gold standard for treating motor symptoms of Parkinson's disease (PD), it presents long-term complications. Deep brain stimulation is effective, but only a small percentage of idiopathic PD patients are eligible. Based on results in animal models and a handful of patients, dorsal column stimulation (DCS) has been proposed as a potential therapy for PD. To date, the long-term effects of DCS in animal models have not been quantified. Here, we report that DCS applied twice a week in rats treated with bilateral 6-OHDA striatal infusions led to a significant improvement in symptoms. DCS-treated rats exhibited a higher density of dopaminergic innervation in the striatum and higher neuronal cell count in the substantia nigra pars compacta compared to a control group. These results suggest that DCS has a chronic therapeutical and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients.
Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.
Brain, behavior, and immunity, 2017

Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis.
Antibody against Small Aggregated Peptide Specifically Recognizes Toxic Aβ-42 Oligomers in Alzheimer's Disease.
ACS chemical neuroscience, 2015

Amyloid-beta (Aβ) oligomers have emerged as the most toxic species in Alzheimer's disease (AD) and other amyloid pathologies. Also, Aβ-42 peptide is more aggregation-prone compared to other Aβ isoforms. Thus, we synthesized a small peptide of repeated sequence containing the last three amino acids, Val-40, Ile-41, and Ala-42 of Aβ-42 that was subsequently aggregated and used to generate a novel antibody, VIA. In this study, we examined human AD and Tg2576 mouse brain samples using VIA in combination with other amyloid-specific antibodies and confirmed the specificity of VIA to oligomeric Aβ-42. Moreover, we found that VIA does not recognize classic amyloid plaques composed of fibrillar Aβ or Aβ-40 ex vivo. Since VIA recognizes a distinct epitope specific to Aβ-42 oligomers, it may have broad use for examining the accumulation of these oligomers in AD and other neurodegenerative diseases. VIA may also be used in immunotherapy studies to prevent neurodegenerative effects associated with Aβ-42 oligomers.
TRPC Channels Mediate a Muscarinic Receptor-Induced Afterdepolarization in Cerebral Cortex.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

Activation of muscarinic cholinergic receptors on pyramidal cells of the cerebral cortex induces the appearance of a slow afterdepolarization that can sustain autonomous spiking after a brief excitatory stimulus. Accordingly, this phenomenon has been hypothesized to allow for the transient storage of memory traces in neuronal networks. Here we investigated the molecular basis underlying the muscarinic receptor-induced afterdepolarization using molecular biological and electrophysiological strategies. We find that the ability of muscarinic receptors to induce the inward aftercurrent underlying the slow afterdepolarization is inhibited by expression of a Galpha(q-11) dominant negative and is also markedly reduced in a phospholipase C beta1 (PLCbeta1) knock-out mouse. Furthermore, we show, using a genetically encoded biosensor, that activation of muscarinic receptor induces the breakdown of phosphatidylinositol 4,5-bisphosphate in pyramidal cells. These results indicate that the Galpha(q-11)/PLCbeta1 cascade plays a key role in the ability of muscarinic receptors to signal the inward aftercurrent. We have shown previously that the muscarinic afterdepolarization is mediated by a calcium-activated nonselective cation current, suggesting the possible involvement of TRPC channels. We find that expression of a TRPC dominant negative inhibits, and overexpression of wild-type TRPC5 or TRPC6 enhances, the amplitude of the muscarinic receptor-induced inward aftercurrent. Furthermore, we find that coexpression of TRPC5 and T-type calcium channels is sufficient to reconstitute a muscarinic receptor-activated inward aftercurrent in human embryonic kidney HEK-293 cells. These results indicate that TRPC channels mediate the muscarinic receptor-induced slow afterdepolarization seen in pyramidal cells of the cerebral cortex and suggest a possible role for TRPC channels in mnemonic processes.
The Emerging Role of HDACs: Pathology and Therapeutic Targets in Diabetes Mellitus.
Cells, 2021

Diabetes mellitus (DM) is one of the principal manifestations of metabolic syndrome and its prevalence with modern lifestyle is increasing incessantly. Chronic hyperglycemia can induce several vascular complications that were referred to be the major cause of morbidity and mortality in DM. Although several therapeutic targets have been identified and accessed clinically, the imminent risk of DM and its prevalence are still ascending. Substantial pieces of evidence revealed that histone deacetylase (HDAC) isoforms can regulate various molecular activities in DM via epigenetic and post-translational regulation of several transcription factors. To date, 18 HDAC isoforms have been identified in mammals that were categorized into four different classes. Classes I, II, and IV are regarded as classical HDACs, which operate through a Zn-based mechanism. In contrast, class III HDACs or Sirtuins depend on nicotinamide adenine dinucleotide (NAD
Behavioral and stereological characterization of Hdc KO mice: Relation to Tourette syndrome.
The Journal of comparative neurology, 2017

A premature termination codon in the human histidine decarboxylase (Hdc) gene has been identified in a family suffering from Guilles de la Tourette syndrome (GTS). In the current study we investigated if mice lacking the histamine producing enzyme HDC share the morphological and cytological phenotype with GTS patients by using magnetic resonance (MRI) and diffusion tensor imaging (DTI), unbiased stereology and immunohistochemistry. Behavior of Hdc knock-out (Hdc KO) mice was assessed in an open field test. The results of stereological, volumetric and DTI analysis measurements showed no significant differences between control and Hdc KO mice. The numbers and distribution of GABAergic parvalbumin or nitric oxide-expressing and cholinergic interneurons were normal in Hdc KO mice. Cortical morphology and layering in adult Hdc KO mice were also preserved. In open field test Hdc KO mice showed impaired exploratory activity and habituation when introduced to novel environment. Our results indicate that Hdc deficiency in mice does not disturb the development of striatal and cortical interneurons and does not lead to the morphological and cytological phenotypes characterized by humans with GTS. Nevertheless, histamine deficiency leads to behavioral alterations probably due to neurotransmitter dysbalance on the level of the striatum.
In the Mind of Dementia: Neurobiological Empathy, Incommensurability, and the Dementia Tojisha Movement in Japan.
Medical anthropology quarterly, 2020

Living in the world's leading superaging society, Japanese are confronted with a tsunami of dementia that has generated fear of becoming mentally incommensurable to oneself and to others. Based on three years of fieldwork in various clinical settings, including a memory clinic in Tokyo, I show how people with dementia (dementia tojishas) and doctors have employed three approaches to overcoming incommensurability: psychotherapeutic, neurobiological, and ecological. With a primary focus on the neurobiological, I show how tojishas and doctors try to cultivate what I call "neurobiological empathy," asking people to imagine not just how to be together with those with dementia but also what it is to be (in the mind of someone) with dementia. Investigating both the effects and limits of the neurobiologization of dementia, I ask how the dementia tojisha movement can work toward diminishing the preexisting fear about dementia and supplementing incommensurability with understanding and empathy.
Histological assessment of optogenetic tools to study fronto-visual and fronto-parietal cortical networks in the rhesus macaque.
Scientific reports, 2020

Optogenetics offers unprecedented possibilities to investigate cortical networks. Yet, the number of successful optogenetic applications in non-human primates is still low, and the consequences of opsin expression in the primate brain are not well documented. We assessed histologically if we can target cerebrocortical networks with three common optogenetic constructs (AAV2/5-CaMKIIα-eNpHR3.0-mCherry, -ChR2-eYFP, -C1V1-mCherry). The frontal eye field or the dorsal premotor area of rhesus macaques were virally injected, and the resulting transduction spread, expression specificity, and opsin trafficking into axons projecting to parietal and visual areas were examined. After variable periods (2-24 months), expression was robust for all constructs at the injection sites. The CaMKIIα promoter driven-expression was predominant, but not exclusive, in excitatory neurons. In the case of eNpHR3.0-mCherry and ChR2-eYFP, opsins were present in axonal projections to target areas, in which sparse, retrogradely transduced neurons could also be found. Finally, the intracellular distribution of opsins differed: ChR2-eYFP had almost exclusive membrane localization, while eNpHR3.0-mCherry and C1V1-mCherry showed additional intracellular accumulations, which might affect neuronal survival in the long-term. Results indicate that all three constructs can be used for local neuronal modulation, but axonal stimulation and long-term use require additional considerations of construct selection and verification.
Intranasal vasopressin modulates resting state brain activity across multiple neural systems: Evidence from a brain imaging machine learning study.
Neuropharmacology, 2021

Arginine vasopressin (AVP), a neuropeptide with widespread receptors in brain regions important for socioemotional processing, is critical in regulating various mammalian social behavior and emotion. Although a growing body of task-based brain imaging studies have revealed the effects of AVP on brain activity associated with emotion processing, social cognition and behaviors, the potential modulations of AVP on resting-state brain activity remain largely unknown. Here, the current study addressed this issue by adopting a machine learning approach to distinguish administration of AVP and placebo, employing the amplitude of low-frequency fluctuation (ALFF) as a measure of resting-state brain activity. The brain regions contributing to the classification were then subjected to functional connectivity and decoding analyses, allowing for a data-driven quantitative inference on psychophysiological functions. Our results indicated that ALFF across multiple neural systems were sufficient to distinguish between AVP and placebo at individual level, with the contributing regions distributed across the social cognition network, sensorimotor regions and emotional processing network. These findings suggest that the role of AVP in socioemotional functioning recruits multiple brain networks distributed across the whole brain rather than specific localized neural pathways. Beyond these findings, the current data-driven approach also opens a novel avenue to delineate neural underpinnings of various neuropeptides or hormones.