Phosphorylation of the neurogenic transcription factor SOX11 on serine 133 modulates neuronal morphogenesis.

The intellectual disability gene, Sox11, encodes for a critical neurodevelopmental transcription factor with functions in precursor survival, neuronal fate determination, migration and morphogenesis. The mechanisms regulating SOX11's activity remain largely unknown. Mass spectrometric analysis uncovered that SOX11 can be post-translationally modified by phosphorylation. Here, we report that phosphorylatable serines surrounding the high-mobility group box modulate SOX11's transcriptional activity. Through Mass Spectrometry (MS), co-immunoprecipitation assays and in vitro phosphorylation assays followed by MS we verified that protein kinase A (PKA) interacts with SOX11 and phosphorylates it on S133. In vivo replacement of SoxC factors in developing adult-generated hippocampal neurons with SOX11 S133 phospho-mutants indicated that phosphorylation on S133 modulates dendrite development of adult-born dentate granule neurons, while reporter assays suggested that S133 phosphorylation fine-tunes the activation of select target genes. These data provide novel insight into the control of the critical neurodevelopmental regulator SOX11 and imply SOX11 as a mediator of PKA-regulated neuronal development.

Probabilistic vs. deterministic fiber tracking and the influence of different seed regions to delineate cerebellar-thalamic fibers in deep brain stimulation.

This study compared tractography approaches for identifying cerebellar-thalamic fiber bundles relevant to planning target sites for deep brain stimulation (DBS). In particular, probabilistic and deterministic tracking of the dentate-rubro-thalamic tract (DRTT) and differences between the spatial courses of the DRTT and the cerebello-thalamo-cortical (CTC) tract were compared. Six patients with movement disorders were examined by magnetic resonance imaging (MRI), including two sets of diffusion-weighted images (12 and 64 directions). Probabilistic and deterministic tractography was applied on each diffusion-weighted dataset to delineate the DRTT. Results were compared with regard to their sensitivity in revealing the DRTT and additional fiber tracts and processing time. Two sets of regions-of-interests (ROIs) guided deterministic tractography of the DRTT or the CTC, respectively. Tract distances to an atlas-based reference target were compared. Probabilistic fiber tracking with 64 orientations detected the DRTT in all twelve hemispheres. Deterministic tracking detected the DRTT in nine (12 directions) and in only two (64 directions) hemispheres. Probabilistic tracking was more sensitive in detecting additional fibers (e.g. ansa lenticularis and medial forebrain bundle) than deterministic tracking. Probabilistic tracking lasted substantially longer than deterministic. Deterministic tracking was more sensitive in detecting the CTC than the DRTT. CTC tracts were located adjacent but consistently more posterior to DRTT tracts. These results suggest that probabilistic tracking is more sensitive and robust in detecting the DRTT but harder to implement than deterministic approaches. Although sensitivity of deterministic tracking is higher for the CTC than the DRTT, targets for DBS based on these tracts likely differ.

Distance between Active Electrode Contacts and Dentatorubrothalamic Tract in Patients with Habituation of Stimulation Effect of Deep Brain Stimulation in Essential Tremor.

Background Some patients under thalamic deep brain stimulation (DBS) for essential tremor (ET) experience habituation of tremor reduction. The nucleus ventralis intermedius (Vim) is the current main target side for ET in DBS. However, the dentatorubrothalamic tract (DRTT) is considered the relevant structure to stimulate. We investigated the distance between the active contact of the DBS electrode and the DRTT and compared this distance in patients with habituation of tremor reduction and good responders. Material and Methods In this retrospective study, we performed deterministic fiber tracking of the DRTT in 6 patients (12 hemispheres) with ET who underwent DBS in the Vim. We subsequently measured the distance between the active contact of the electrode and the ipsilateral DRTT in both hemispheres. The clinical tremor response of those 6 patients was analyzed accordingly. Results The distance between the active contact and the DRTT in patients with better and constant clinical tremor reduction was shorter (mean distance: 2.9 ± 2.2 mm standard deviation [SD]) than in patients who showed habituation of their response (mean distance: 6.1 ± 3.9 mm SD). After re-placement of a thalamic electrode inside the DRTT in one patient who experienced unsatisfying tremor reduction due to habituation of stimulation, the tremor alleviation was significant and persistent at a 13-month follow-up. Conclusion This retrospective analysis suggests that recurrence of ET tremor under chronic DBS might be associated with a larger distance between the DRTT and the active lead contact, in comparison with the smaller distances in patients with persistently good tremor control.

Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis.

Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus.

DTI-based deterministic fibre tracking of the medial forebrain bundle.

BACKGROUND: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) was reported to reduce symptoms in psychiatric disorders. The aim of our study was to find standardised parameters for diffusion tensor imaging (DTI) based fibre tracking to reliably visualise the MFB. METHODS: Twenty-two cerebral hemispheres in 11 patients were investigated. Three different regions of interest (ROIs) were defined as seed regions for fibre tracking: the ipsilateral and contralateral superior cerebellar peduncle (SCP) and the nucleus raphe dorsalis (NRD). From each seed region the fibres were followed separately through the ventral tegmental area (VTA = second ROI) and their further courses and volumina were documented and compared. Minimal fibre length was set at 30 mm and the FA threshold at 0.12. RESULTS: The fibre tracts starting in seed regions in the ipsilateral SCP and the NRD follow a similar course along the lateral wall of the third ventricle (hypothalamus) and the anterior limb of the internal capsule (ALIC) to inferior fronto-medial brain areas. These fibres are in accordance with the course of the MFB as described in various anatomical atlases. Consistently, a branch leaves the main fibre tract laterally to take a course through the capsula externa to the temporo-parietal cortex. Fibre tracts starting from the contralateral SCP follow a more superior and lateral course, including the dentato-rubro-thalamic and the pyramidal tract. CONCLUSIONS: Deterministic fibre tracking with standardised ROIs provides constant and reproducible delineations of the medial forebrain bundle. Its visualisation might help to adjust targeting in DBS for psychiatric disorders.

Deep brain stimulation for essential tremor: targeting the dentato-rubro-thalamic tract?

OBJECTIVE: The aim of our study was to evaluate the influence of the stimulation site relative to the dentato-rubro-thalamic tract (DRTT) on the alleviation of tremor in deep brain stimulation. METHODS: Ten DRTTs in five patients were investigated using preoperative diffusion tensor imaging (DTI). Regions of interest for fiber tracking were located in the cerebellar dentate nucleus, the superior cerebellar peduncle and the contralateral red nucleus. The position and distance of all intraoperative stimulation sites to the DRTT were measured and correlated to the amount of tremor reduction. RESULTS: Nine of 10 DRTTs could be identified using DTI-based fiber tracking. Better tremor reduction was achieved in locations in or posterior and lateral to the DRTT than in medial and anterior positions (p = 0.001). Stimulation sites inferior to and in the DRTT achieved better results than locations superior to the DRTT (p < 0.05). The vicinity of the stimulation site to the DRTT did not correlate with tremor alleviation. DISCUSSION: In deep brain stimulation targeting for thalamic stimulation sites is limited to statistical, atlas-based coordinates. Diffusion tensor imaging and fiber tracking was used to visualize the dentato-rubro-thalamic tract as a potential, individualized target structure. However, we could not demonstrate that contacts closer to the DRTT provided better clinical effects than distant contacts, in any given direction. DTI sequences with a higher number of read-out directions, probabilistic fiber tracking and three Tesla MRI scanners may lead to different results in the depiction of the chosen fiber tract and may provide a better correlation with stimulation effects. CONCLUSIONS: The results do not provide sufficient evidence to define the DRTT as a new DBS-target for tremor. Further investigations on different fiber tracts, DTI sequences, and fiber tracking algorithms are mandatory.

Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain.

Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity.

The variability of atlas-based targets in relation to surrounding major fibre tracts in thalamic deep brain stimulation.

BACKGROUND: In essential tremor (ET), the main target for deep brain stimulation (DBS) is the thalamic ventralis intermedius nucleus (Vim). This target cannot be identified on conventional magnetic resonance imaging (MRI). Therefore, targeting depends on probabilistic coordinates derived from stereotactic atlases. The goal of our study was to investigate the variability of atlas-based Vim targets in relation to surrounding major fibre tracts. METHODS: With the MRI and computed tomography (CT) scan data of ten patients who underwent DBS, we planned atlas based Vim targets in both hemispheres. We also performed deterministic fibre-tracking with diffusion tensor imaging (DTI) of the dentato-rubro-thalamic tract (DRTT), pyramidal tract (PT) and lemniscus medialis (LM) in all 20 hemispheres. Subsequently, we measured the distance from the atlas-based Vim target to each tract along the medial/lateral (x-coordinate), anterior/posterior (y-coordinate) and superior/inferior axis (z-coordinate). RESULTS: Seventeen out of 20 DRTTs could be depicted with our standardised DTI/fibre-tracking parameters. The PT and the LM could be displayed in all 20 hemispheres. The atlas-based Vim target was found inside the DRTT in 11 (concerning the x-coordinate) and 10 hemispheres (concerning the z-coordinate). Regarding the anterior/posterior direction, the target was posterior to the DRTT in 11 cases. In 19 hemispheres the Vim target was located medial and superior to the PT and in 17 hemispheres posterior to it. Concerning the LM, the Vim target was found inside the LM in 16 (regarding the x-coordinate) and in 14 cases (regarding the z-coordinate). In eight cases it was located inside and in 12 cases anterior to the LM concerning the y-coordinate. CONCLUSIONS: We found a considerable variability of the location of atlas-based target points of the ventralis intermedius nucleus in relation to neighbouring major fibre tracts in individual patients. These results suggest that individualised targeting to structures not directly visible on conventional MRI is necessary.

Predictors of facet joint syndrome after lumbar disc surgery.

Postoperative facet joint syndrome (pFJS) requiring intervention is a common problem following lumbar disc surgery (LDS). The aim of this retrospective study was to identify possible predictors, surgical aspects or individual characteristics that may contribute to the development of pFJS and may allow prevention of this frequent postoperative problem. We included 509 patients who underwent open, microsurgical discectomy in our neurosurgical department between 2006 and 2009 and who presented to our outpatient clinic for follow-up. We recorded gender, age, preoperative and postoperative clinical and neurological status, surgical technique, duration of the surgical procedure, disc herniation relapse, rehabilitation treatment and development of pFJS. Forty-three patients (8.4%) developed clinically evident pFJS, confirmed by a successful facet joint injection. Patients with pFJS were significantly older than those without pFJS (55.7 years compared with 50.9 years; p=0.03) and had more frequent recurrent disc herniation (p=0.001). Furthermore, the duration of the surgical procedure (p=0.01), intraoperative and postoperative complications (for example, postoperative bleeding, dural injury; p=0.001) and general comorbidity (p=0.001) were associated with pFJS. In addition, an extended discectomy compared with sequesterotomy (p=0.049) and rehabilitation treatment compared with no rehabilitation (p=0.019) were correlated to pFJS in the multivariate analysis. Thus, we were able to identify factors associated with the development of pFJS following LDS: advanced age, long operative time, intraoperative complications, history of recurrent disc prolapse, discectomy and lack of rehabilitation. Our results characterize a profile for patients at high risk for the development of clinically evident pFJS.

Expression of fatty acid synthase in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which starts with simple hepatic steatosis and may progress toward inflammation (nonalcoholic steatohepatitis [NASH]). Fatty acid synthase (FASN) catalyzes the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. The aim of this study was to analyze the correlation between hepatic steatosis and inflammation with FASN expression. In vitro incubation of primary human hepatocytes with fatty acids dose-dependently induced cellular lipid-accumulation and FASN expression, while stimulation with TNF did not affect FASN levels. Further, hepatic FASN expression was significantly increased in vivo in a murine model of hepatic steatosis without significant inflammation but not in a murine NASH model as compared to control mice. Also, FASN expression was not increased in mice subjected to bile duct ligation, an experimental model characterized by severe hepatocellular damage and inflammation. Furthermore, FASN expression was analyzed in 102 human control or NAFLD livers applying tissue micro array technology and immunohistochemistry, and correlated significantly with the degree of hepatic steatosis, but not with inflammation or ballooning of hepatocytes. Quantification of FASN mRNA expression in human liver samples confirmed significantly higher FASN levels in hepatic steatosis but not in NASH, and expression of SREBP1, which is the main transcriptional regulator of FASN, paralleled FASN expression levels in human and experimental NAFLD. In conclusion, the transcriptional induction of FASN expression in hepatic steatosis is impaired in NASH, while hepatic inflammation in the absence of steatosis does not affect FASN expression, suggesting that FASN may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD.

GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus.

Survival and integration of new neurons in the hippocampal circuit are rate-limiting steps in adult hippocampal neurogenesis. Neuronal network activity is a major regulator of these processes, yet little is known about the respective downstream signaling pathways. Here, we investigate the role of cAMP response element-binding protein (CREB) signaling in adult hippocampal neurogenesis. CREB is activated in new granule neurons during a distinct developmental period. Loss of CREB function in a cell-autonomous manner impairs dendritic development, decreases the expression of the neurogenic transcription factor NeuroD and of the neuronal microtubule-associated protein, doublecortin (DCX), and compromises the survival of newborn neurons. In addition, GABA-mediated excitation regulates CREB activation at early developmental stages. Importantly, developmental defects after loss of GABA-mediated excitation can be compensated by enhanced CREB signaling. These results indicate that CREB signaling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation.