| 1. |
- Benlloch, Jose M., et al.
(författare)
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The MINDVIEW project : First results
- 2018
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Ingår i: European psychiatry. - : Cambridge University Press (CUP). - 0924-9338 .- 1778-3585. ; 50, s. 21-27
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Tidskriftsartikel (refereegranskat)abstract
- We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.
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| 2. |
- Bikovski, Lior, et al.
(författare)
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Lessons, insights and newly developed tools emerging from behavioral phenotyping core facilities
- 2020
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270 .- 1872-678X. ; 334
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Forskningsöversikt (refereegranskat)abstract
- Scientific investigations, in general, and research in neuroscience, in particular, are becoming ever more complex and require the integration of different techniques. Behavioral assays, which are among the most frequently used methodologies in neuroscience, nowadays rely on advanced, sophisticated technologies that require proficient application. Therefore, behavioral core facilities are becoming essential support units, as they provide the specialized expert research services needed to conduct advanced neuroscience. We here review the lessons learned and insights gathered from managing behavioral core facilities in different academic research institutes. This review addresses several issues, including: the advantages of behavioral core facilities, considerations for establishing a behavioral core facility, and the methodological advances made through calibration and standardization of assay protocols and the development of new assays. Collectively, the review highlights the benefits of both working within and collaborating with behavioral core facility units and emphasizes the potential progress in neuro-phenotyping that such facilities provide.
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| 3. |
- Bogatikov, Evgenii, 1982-
(författare)
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Towards Better Understanding of Etiological Mechanisms at the Neuromuscular Junction
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The neuromuscular junction (NMJ) serves as a model for understanding the mechanisms that determine communication between neurons and their target cells. Disorders of the NMJ can be either autoimmune or genetic (hereditary). The autoimmune disorder myasthenia gravis (MG) is caused by antibodies against the presynaptic nerve terminal or the postsynaptic muscle membrane, which make up the NMJ. The most common antibodies are directed against the acetylcholine receptor (AChR) or muscle specific tyrosine kinase (MuSK). An alternative to expand on preclinical in-vivo methods for studying mechanisms underlying diseases of neuromuscular transmission is to apply physiologic in-vitro models that would allow tissue-tissue as well as cell-cell interactions. A system that would allow cell-cell interactions in a biological fashion is the micro-electrode array (MEA) chip that allows co-culturing of motor neurons and muscle cells.The primary hypothesis is that the suggested MEA can be used in creating a reliable model for healthy and diseased NMJ, allowing for manipulations and treatment assays. The secondary hypothesis is that small non-coding RNA, so called microRNAs (miRNA) have a specific role in neuromuscular transmission and in MG.Study I demonstrated a method of long-term muscle cell culture on the MEA chips, which allows us to trace the development of muscle cells through the observation of their electrical activity at subcellular resolution. The maturation of skeletal muscle tissue was accompanied by a gradual increase in the amplitude and frequency of extracellular individual electrical spikes. The mature muscle tissue demonstrated the steady electrical activity with synchronized spike propagation in different directions across the chip.Study II showed a specific upregulated profile of miRNAs in the muscles of MuSK antibody seropositive MG mice. Transfection of these miRNAs, miR-1933 and miR-1930, promoted downregulation of several proteins and further confirmation with qPCR revealed a specific blocking of IMPA1 and MRPL27, which are involved in intracellular signal transduction and mitochondrial biogenesis in skeletal muscles.Study III revealed no correlation between the morphology of skeletal muscle cells and their electrical activity at an early developmental stage. However, the application of recombinant rat agrin increased the number of AChRs clusters in the culture of skeletal muscle and promoted a higher degree of spontaneous activity.
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| 4. |
- Boije, Henrik, et al.
(författare)
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Origin and circuitry of spinal locomotor interneurons generating different speeds.
- 2018
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Ingår i: Current Opinion in Neurobiology. - : Elsevier BV. - 0959-4388 .- 1873-6882. ; 53, s. 16-21
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Tidskriftsartikel (refereegranskat)abstract
- The spinal circuitry governing the undulatory movements of swimming vertebrates consist of excitatory and commissural inhibitory interneurons and motor neurons. This locomotor network generates the rhythmic output, coordinate left/right alternation, and permit communication across segments. Through evolution, more complex movement patterns have emerged, made possible by sub-specialization of neural populations within the spinal cord. Walking tetrapods use a similar basic circuitry, but have added layers of complexity for the coordination of intralimbic flexor and extensor muscles as well as interlimbic coordination between the body halves and fore/hindlimbs. Although the basics of these circuits are known there is a gap in our knowledge regarding how different speeds and gaits are coordinated. Analysing subpopulations among described neuronal populations may bring insight into how changes in locomotor output are orchestrated by a hard-wired network.
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| 5. |
- Carneiro, Miguel, et al.
(författare)
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A loss-of-function mutation in RORB disrupts saltatorial locomotion in rabbits
- 2021
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- Saltatorial locomotion is a type of hopping gait that in mammals can be found in rabbits, hares, kangaroos, and some species of rodents. The molecular mechanisms that control and fine-tune the formation of this type of gait are unknown. Here, we take advantage of one strain of domesticated rabbits, the sauteur d’Alfort, that exhibits an abnormal locomotion behavior defined by the loss of the typical jumping that characterizes wild-type rabbits. Strikingly, individuals from this strain frequently adopt a bipedal gait using their front legs. Using a combination of experimental crosses and whole genome sequencing, we show that a single locus containing the RAR related orphan receptor B gene (RORB) explains the atypical gait of these rabbits. We found that a splice-site mutation in an evolutionary conserved site of RORB results in several aberrant transcript isoforms incorporating intronic sequence. This mutation leads to a drastic reduction of RORB-positive neurons in the spinal cord, as well as defects in differentiation of populations of spinal cord interneurons. Our results show that RORB function is required for the performance of saltatorial locomotion in rabbits.Author summaryRabbits and hares have a characteristic jumping gait composed of an alternate rhythmical movement of the forelimbs and a synchronous bilateral movement of the hindlimbs. We have now characterized a recessive mutation present in a specific strain of domestic rabbits (sauteur d’Alfort) that disrupts the jumping gait. The mutation causing this defect in locomotion pattern occurs in the gene coding for the transcription factor RORB that is normally expressed in many regions of the nervous system especially in the spinal cord dorsal horn. Our results show that expression of RORB is drastically reduced in the spinal cord of affected rabbits which results in a developmental defect. This study is an advance in our understanding how locomotion is controlled in vertebrates.
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| 6. |
- Ciralli, Barbara, et al.
(författare)
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Unraveling the role of Slc10a4 in auditory processing and sensory motor gating : Implications for neuropsychiatric disorders?
- 2024
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Ingår i: Progress in Neuro-psychopharmacology and Biological Psychiatry. - : Elsevier. - 0278-5846 .- 1878-4216. ; 131
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPsychiatric disorders, such as schizophrenia, are complex and challenging to study, partly due to the lack of suitable animal models. However, the absence of the Slc10a4 gene, which codes for a monoaminergic and cholinergic associated vesicular transporter protein, in knockout mice (Slc10a4−/−), leads to the accumulation of extracellular dopamine. A major challenge for studying schizophrenia is the lack of suitable animal models that accurately represent the disorder. We sought to overcome this challenge by using Slc10a4−/− mice as a potential model, considering their altered dopamine levels. This makes them a potential animal model for schizophrenia, a disorder known to be associated with altered dopamine signaling in the brain.MethodsThe locomotion, auditory sensory filtering and prepulse inhibition (PPI) of Slc10a4−/− mice were quantified and compared to wildtype (WT) littermates. Intrahippocampal electrodes were used to record auditory event-related potentials (aERPs) for quantifying sensory filtering in response to paired-clicks. The channel above aERPs phase reversal was chosen for reliably comparing results between animals, and aERPs amplitude and latency of click responses were quantified. WT and Slc10a4−/− mice were also administered subanesthetic doses of ketamine to provoke psychomimetic behavior.ResultsBaseline locomotion during auditory stimulation was similar between Slc10a4−/− mice and WT littermates. In WT animals, normal auditory processing was observed after i.p saline injections, and it was maintained under the influence of 5 mg/kg ketamine, but disrupted by 20 mg/kg ketamine. On the other hand, Slc10a4−/− mice did not show significant differences between N40 S1 and S2 amplitude responses in saline or low dose ketamine treatment. Auditory gating was considered preserved since the second N40 peak was consistently suppressed, but with increased latency. The P80 component showed higher amplitude, with shorter S2 latency under saline and 5 mg/kg ketamine treatment in Slc10a4−/− mice, which was not observed in WT littermates. Prepulse inhibition was also decreased in Slc10a4−/− mice when the longer interstimulus interval of 100 ms was applied, compared to WT littermates.ConclusionThe Slc10a4−/− mice responses indicate that cholinergic and monoaminergic systems participate in the PPI magnitude, in the temporal coding (response latency) of the auditory sensory gating component N40, and in the amplitude of aERPs P80 component. These results suggest that Slc10a4−/− mice can be considered as potential models for neuropsychiatric conditions.
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| 7. |
- Defourny, Jean, et al.
(författare)
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EphA4-ADAM10 Interplay Patterns the Cochlear Sensory Epithelium through Local Disruption of Adherens Junctions
- 2019
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 11, s. 246-257
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Tidskriftsartikel (refereegranskat)abstract
- The cochlear sensory epithelium contains a functionally important triangular fluid-filled space between adjacent pillar cells referred to as the tunnel of Corti. However, the molecular mechanisms leading to local cell-cell separation during development remain elusive. Here we show that EphA4 associates with ADAM10 to promote the destruction of E-cadherin-based adhesions between adjacent pillar cells. These cells fail to separate from each other, and E-cadherin abnormally persists at the pillar cell junction in EphA4 forward-signaling-deficient mice, as well as in the presence of ADAM10 inhibitor. Using immunolabeling and an in situ proximity ligation assay, we found that EphA4 forms a complex with E-cadherin and its sheddase ADAM10, which could be activated by ephrin-B2 across the pillar cell junction to trigger the cleavage of E-cadherin. Altogether, our findings provide a new molecular insight into the regulation of adherens junctions, which might be extended to a variety of physiological or pathological processes.
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| 8. |
- del Pozo, Ana, et al.
(författare)
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Behavioral Characterization of dmrt3a Mutant Zebrafish Reveals Crucial Aspects of Vertebrate Locomotion through Phenotypes Related to Acceleration
- 2020
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Ingår i: eNeuro. - 2373-2822. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Vertebrate locomotion is orchestrated by spinal interneurons making up a central pattern generator. Proper coordination of activity, both within and between segments, is required to generate the desired locomotor output. This coordination is altered during acceleration to ensure the correct recruitment of muscles for the chosen speed. The transcription factor Dmrt3 has been proposed to shape the patterned output at different gaits in horses and mice. Here, we characterized dmrt3a mutant zebrafish, which showed a strong, transient, locomotor phenotype in developing larvae. During beat-and-glide swimming, mutant larvae showed fewer and shorter movements with decreased velocity and acceleration. Developmental compensation likely occurs as the analyzed behaviors did not differ from wild-type at older larval stages. However, analysis of maximum swim speed in juveniles suggests that some defects persist within the mature locomotor network of dmrt3a mutants. Our results reveal the pivotal role Dmrt3 neurons play in shaping the patterned output during acceleration in vertebrates.
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| 9. |
- Enjin, Anders, et al.
(författare)
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Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell-motor neuron circuit
- 2017
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 37:23, s. 5634-5647
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Tidskriftsartikel (refereegranskat)abstract
- When activating muscles, motor neurons in the spinal cord also activate Renshaw cells, which provide recurrent inhibitory feedback to the motor neurons. The tight coupling with motor neurons suggests that Renshaw cells have an integral role in movement, a role that is yet to be elucidated. Here we used the selective expression of the nicotinic cholinergic receptor α2 (Chrna2) in mice to genetically target the vesicular inhibitory amino acid transporter (VIAAT) in Renshaw cells. Loss of VIAAT from Chrna2Cre-expressing Renshaw cells did not impact any aspect of drug-induced fictive locomotion in the neonatal mouse or change gait, motor coordination, or grip strength in adult mice of both sexes. However, motor neurons from neonatal mice lacking VIAAT in Renshaw cells received spontaneous inhibitory synaptic input with a reduced frequency, showed lower input resistance, and had an increased number of proprioceptive glutamatergic and calbindin-labeled putative Renshaw cell synapses on their soma and proximal dendrites. Concomitantly, Renshaw cells developed with increased excitability and a normal number of cholinergic motor neuron synapses, indicating a compensatory mechanism within the recurrent inhibitory feedback circuit. Our data suggest an integral role for Renshaw cell signaling in shaping the excitability and synaptic input to motor neurons.
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| 10. |
- Enjin, Anders, et al.
(författare)
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Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells
- 2010
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 518:12, s. 2284-2304
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Tidskriftsartikel (refereegranskat)abstract
- Spinal cholinergic neurons are critical for motor function in both the autonomic and somatic nervous systems and are affected in spinal cord injury and in diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Using two screening approaches and in situ hybridization, we identified 159 genes expressed in typical cholinergic patterns in the spinal cord. These include two general cholinergic neuron markers, one gene exclusively expressed in motor neurons and nine genes expressed in unknown subtypes of somatic motor neurons. Further, we present evidence that Chondrolectin (Chodl) is a novel genetic marker for putative fast motor neurons and that estrogen-related receptor b (ERRb) is a candidate genetic marker for slow motor neurons. In addition, we suggest paired-like homeodomain transcription factor 2 (Pitx2) as a marker for cholinergic partition cells.
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