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Braak and Del Tredici have proposed that typical Parkinson disease (PD) has its origins in the olfactory bulb and gastrointestinal tract. However, the role of the olfactory system has insufficiently been explored in the pathogeneses of PD and Alzheimer disease (AD) in laboratory models. Here, we demonstrate applications of a new method to process mouse heads for microscopy by sectioning, mounting, and staining whole skulls (‘holocranohistochemistry’). This technique permits the visualization of the olfactory system from the nasal cavity to mitral cells and dopamine-producing interneurons of glomeruli in the olfactory bulb. We applied this method to two specific goals: first, to visualize PD- and AD-linked gene expression in the olfactory system, where we detected abundant, endogenous α-synuclein and tau expression in the olfactory epithelium. Furthermore, we observed amyloid-β plaques and proteinase-K-resistant α-synuclein species, respectively, in cranial nerve-I of APP - and human SNCA -over-expressing mice. The second application of the technique was to the modeling of gene–environment interactions in the nasal cavity of mice. We tracked the infection of a neurotropic respiratory-enteric-orphan virus from the nose pad into cranial nerves-I (and -V) and monitored the ensuing brain infection. Given its abundance in the olfactory epithelia, we questioned whether α-synuclein played a role in innate host defenses to modify the outcome of infections. Indeed, Snca -null mice were more likely to succumb to viral encephalitis versus their wild-type littermates. Moreover, using a bacterial sepsis model, Snca -null mice were less able to control infection after intravenous inoculation with Salmonella typhimurium . Together, holocranohistochemistry enabled new discoveries related to α-synuclein expression and its function in mice. Future studies will address: the role of Mapt and mutant SNCA alleles in infection paradigms; the contribution of xenobiotics in the initiation of idiopathic PD; and the safety to the host when systemically targeting α-synuclein by immunotherapy.

Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relatively poorly understood pathophysiology. To determine the relationship between clinical tremor severity and structural magnetic resonance imaging parameters. Eleven patients with clinically definite MS and right-sided upper limb tremor were studied. Tremor severity was assessed using the Bain score (overall severity, writing, and Archimedes spiral drawing). Cerebellar dysfunction was assessed using the Scale for the Assessment and Rating of Ataxia. Dystonia was assessed using the Global Dystonia Scale adapted for upper limb. For all subjects, volume was calculated for the thalamus from T1-weighted volumetric scans using Freesurfer. Superior cerebellar peduncle (SCP) cross-sectional areas were measured manually. The presence of lesions was visually determined and the lesion volumes were calculated by the lesion growth algorithm as implemented in the Lesion Segmentation Toolbox. Right thalamic volume negatively correlated with Bain tremor severity score ( ρ  = − 0.65, p  = 0.03). Left thalamic volume negatively correlated with general Bain tremor severity score ( ρ  = − 0.65, p  = 0.03) and the Bain writing score ( ρ  = − 0.65, p  = 0.03). Right SCP area negatively correlated with Bain writing score ( ρ  = − 0.69, p  = 0.02). Finally, Bain Archimedes score was significantly higher in patients with lesions in the contralateral thalamus. Whole brain lesion load showed no relationship with tremor severity. These results implicate degeneration of key structures within the cerebello-thalamic pathway as pathological substrates for tremor in MS patients.

A tissue microarray (TMA) has previously been developed for use in assessment of neurodegenerative diseases. We investigated the variation of pathology loads in semi-quantitative score categories and how pathology load related to disease progression. Post-mortem tissue from 146 cases were used; Alzheimer’s disease (AD) ( n  = 36), Lewy body disease (LBD) ( n  = 56), mixed AD/dementia with Lewy bodies ( n  = 14) and controls ( n  = 40). TMA blocks (one per case) were constructed using tissue cores from 15 brain regions including cortical and subcortical regions. TMA tissue sections were stained for hyperphosphorylated tau (HP- T ), β amyloid and α-synuclein (αsyn), and quantified using an automated image analysis system. Cases classified as Braak stage VI displayed a wide variation in HP- T pathology in the entorhinal cortex (interquartile range 4.13–44.03%). The interquartile range for β amyloid in frontal cortex in cases classified as Thal phase 5 was 6.75–17.03% and for αsyn in the cingulate in cases classified as McKeith neocortical LBD was 0.04–0.58%. In AD and control cases, HP- T load predicted the Braak stage ( p  < 0.001), β amyloid load predicted Thal phase ( p  < 0.001) and αsyn load in LBD cases predicted McKeith type of LBD ( p  < 0.001). Quantitative data from TMA assessment highlight the range in pathological load across cases classified with ‘severe’ pathology and is beneficial to further elucidate the heterogeneity of neurodegenerative diseases. Quantifying pathology in multiple brain regions may allow identification of novel clinico-pathological phenotypes for the improvement of intra vitam stratification of clinical cohorts according to underlying pathologies.

α-Spinasterol is a plant-derived compound which was reported to act as a selective antagonist for the transient receptor potential vanilloid 1 (TRPV1) receptor. Several studies revealed that the TRPV1 receptors might modulate seizure activity in animal models of seizures and epilepsy. The aim of the present study was to investigate the effect of α-spinasterol on the seizure threshold in three acute models of seizures, i.e., in the intravenous (i.v.) pentylenetetrazole (PTZ) seizure test, in the maximal electroshock seizure threshold (MEST) test and in the model of psychomotor seizures induced by 6 Hz stimulation in mice. Our results revealed significant anticonvulsant effect of α-spinasterol in all the used seizure tests. In the i.v. PTZ test, statistically significant elevation was noted in case of the threshold for myoclonic twitches (doses of 0.1–1 mg/kg) and generalized clonus seizures (doses of 0.5 and 1 mg/kg) but not for tonic seizures. The studied TRPV1 antagonist also increased the threshold for tonic hindlimb extension in the MEST (doses of 0.5 and 1 mg/kg) and 6 Hz psychomotor seizure (doses of 0.1 and 0.5 mg/kg) tests in mice. Furthermore, α-spinasterol did not produce any significant impairment of motor coordination (assessed in the chimney test) and muscular strength (investigated in the grip-strength test) and it did not provoke significant changes in body temperature in mice. Based on the results of our study and the fact that α-spinasterol is characterized by good blood–brain permeability, we postulate further investigation of this compound to precisely evaluate mechanism of its anticonvulsant action and opportunity of its usage in clinical practice.

An extensive literature has detailed how maltreatment experience impacts brain structure in children and adolescents. However, there is a dearth of studies on the influence of maltreatment on surface based indices, and to date no study has investigated how sex influences the impact of maltreatment on cortical thickness, surface area and local gyrification. We investigated sex differences in these measures of cortical structure in a large community sample of children aged 10–14 years ( n  = 122) comprising 62 children with verified maltreatment experience and 60 matched non-maltreated controls. The maltreated group relative to the controls presented with a pattern of decreased cortical thickness within a region of right anterior cingulate, orbitofrontal cortex and superior frontal gyrus; decreased surface area within the right inferior parietal cortex; and increased local gyrification within left superior parietal cortex. This atypical pattern of cortical structure was similar across males and females. An interaction between maltreatment exposure and sex was found only in local gyrification, within two clusters: the right tempo-parietal junction and the left precentral gyrus. These findings suggest that maltreatment impacts cortical structure in brain areas associated with emotional regulation and theory of mind, with few differences between the sexes.

The aim of this study was to characterize the influence of WIN 55,212-2 (WIN—a non-selective cannabinoid CB 1 and CB 2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam ( P  < 0.001), phenobarbital ( P  < 0.05) and valproate ( P  < 0.05), but not that of clobazam in the mouse 6 Hz model. Moreover, WIN (2.5 mg/kg) significantly potentiated the anticonvulsant action of clonazepam ( P  < 0.01), but not that of clobazam, phenobarbital or valproate in the 6 Hz test in mice. None of the investigated combinations of WIN with antiepileptic drugs was associated with any concurrent adverse effects with regard to motor performance, learning or muscular strength. Pharmacokinetic experiments revealed that WIN had no impact on total brain concentrations of antiepileptic drugs in mice. These preclinical data would suggest that WIN in combination with clonazepam, phenobarbital and valproate is associated with beneficial anticonvulsant pharmacodynamic interactions in the mouse 6 Hz-induced psychomotor seizure test.

Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-naïve HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95 % CI 1.72–8.96; p  = 0.001, Fishers exact test). 42.6 % HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5 % uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9 %, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.

Application of freezing temperatures to the temporal branch of the facial nerve can temporarily inhibit motor nerve conduction, resulting in inhibition of voluntary contraction of the frontalis and glabella muscle groups. This feasibility study demonstrates the reduction in motility of muscle groups through application of low temperatures to nerves in a rat model. Twenty-seven adult female Sprague–Dawley rats received cryotreatment to the tibial nerve of the hind limb, and the contralateral limb was left untreated as a negative control. The use of a cold temperature application (−59 ± 8 °C for 60 s) onto the rat tibial nerve resulted in temporary reduction of physiological function of the hind limb. Histological observations of the nerve revealed demyelination and axonal degeneration by 2 weeks post-treatment followed by complete axonal regeneration and remyelination at 16 weeks. Application of low temperatures to peripheral motor nerves resulted in temporary denervation and loss of function of the treated hind limb. Low temperature treatment on motor nerves did not result in any permanent or long-term changes to function and structure of the nerves.

To better understand the relationship of repeated exposure to adversity during early development as a risk factor for refractory depression, we exposed pregnant female rats to ethanol and the resulting pups to corticosterone during adolescence. A stressful forced swim test was then used to induce depression-like behavior. The adolescent rat brains were examined for the possible therapeutic benefit of a combination of sertraline, an antidepressant, and neural stem cells (NSCs) complexed with atelocollagen in relation to the level of GABAergic interneuron and synaptic protein density in different brain regions. The combined exposures of prenatal and adolescent stress resulted in a reduction in parvalbumin (PV)-positive phenotype of GABAergic interneurons and reduced postsynaptic density protein 95 (PSD-95) levels in the anterior cingulate cortex, amygdala, and hippocampus. Treatments with sertraline and NSCs reversed the reductions in PV-positive cells and PSD-95 levels. Furthermore, the combined treatment of sertraline and NSCs resulted in reduced depressive-like behaviors. These experiments underscore a potentially important role for synaptic remodeling and GABAergic interneuron genesis in the treatment of refractory depression and highlight the therapeutic potential of stem cell and pharmacological combination treatments for refractory depression.

Recent studies of vascular adhesion protein-1 (VAP-1) have greatly advanced our understanding of the important role this protein plays in the establishment and progression of inflammatory disease. To facilitate more detailed studies on the function of VAP-1, we developed a GFP-fusion protein that enabled us to monitor the trafficking of the protein in three selected cell types: hepatic sinusoidal endothelial cells, liver myofibroblasts and an hepatic stellate cell line (LX-2). The fusion protein was detected as punctate cytoplasmic GFP staining, but was present only at low levels at the cell surface in all cell types studied. The subcellular distribution of the protein was not altered in a catalytically inactive mutant form of the protein (Tyr471Phe) or in the presence of exogenous VAP-1 substrate (methylamine) or inhibitor (semicarbazide). The GFP-VAP-1 protein was localized to the Golgi apparatus (GM-130), endoplasmic reticulum (GRP94) and early endosomes (EEA-1). Additional staining for VAP-1 revealed that the overexpressed protein was also present in vesicles that were negative for GFP fluorescent signal and did not express EEA-1. We propose that these vesicles are responsible for recycling the fusion protein and that the fluorescence of the GFP moiety is quenched at the low pH within these vesicles. This feature of the protein makes it well suited for live cell imaging studies where we wish to track protein that is being actively trafficked within the cell in preference to that which is being recycled.