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The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission. [ABSTRACT FROM AUTHOR]

DST is a gene whose alternative splicing yields epithelial, neuronal, and muscular isoforms. The autosomal recessive Dstdt (dystonia musculorum) spontaneous mouse mutation causes degeneration of spinocerebellar tracts as well as peripheral sensory nerves, dorsal root ganglia, and cranial nerve ganglia. In addition to Dstdt mutants, axonopathy and neurofilament accumulation in perikarya are features of two other murine lines with spontaneous Dst mutations, targeted Dst knockout mice, DstTg4 transgenic mice carrying two deleted Dst exons, DstGt mice with trapped actin-binding domain-containing isoforms, and conditional Schwann cell-specific Dst knockout mice. As a result of nerve damage, Dstdt mutants display dystonia and ataxia, as seen in several genetically modified models and their motor coordination deficits have been quantified along with the spontaneous Dst nonsense mutant, the conditional Schwann cell-specific Dst knockout, the conditional DstGt mutant, and the Dst-b isoform specific Dst mutant. Recent findings in humans have associated DST mutations of the Dst-b isoform with hereditary sensory and autonomic neuropathies type 6 (HSAN-VI). These data should further encourage the development of genetic techniques to treat or prevent ataxic and dystonic symptoms. [ABSTRACT FROM AUTHOR]

The Maier 3-table task comprises three phases conducted each day. During the exploration phase, rats explore the entire apparatus. During the information phase, the rats are placed on one of the three tables where food is found. During the test phase, the animals are placed at the starting point on one of the two remaining tables and must enter the goal table where they previously ate. The acquisition of the Maier 3-table task was slowed down after lesions of the septum, fornix, hippocampus, medial prefrontal cortex, or posterior parietal cortex. Because of its time-consuming nature, the Maier 3-table task has more recently been superseded by appetitive matching-to-place in Y- or T-mazes or the circular water maze, because experimenters skip over the exploration phase. Nevertheless, like the Maier 3-table task, the acquisition of the Y- or T-maze matching-to-place task was retarded after lesions of the medial septum or medial prefrontal cortex, more particularly its prelimbic-infralimbic part. Like the previous task, the water-maze version is sensitive to lesions of the medial septum or retrosplenial cortex. Despite methodological differences between the three procedures, these results indicate common neurobiological bases of matching-to-place learning. [ABSTRACT FROM AUTHOR]

In mice, rats, and rabbits, vigorous jumping and hyperexcitability occur at the popcorn stage of postnatal development. In view of subcortical structures appearing before cortical ones, the trait is deemed to occur at the maturation time of ascending excitatory projections from the brainstem and to disappear at the maturation time of descending inhibitory projections from the forebrain. There is evidence that the popcorn stage may be due in part to the lack of a cholinergic influence on dopamine systems. Based mostly on results found in adult mice and rats, there may also be a role for cortico-subcortical systems that include the cerebellum and basal ganglia requiring the influence of biogenic amines, glutamate, and endocannabinoids. [ABSTRACT FROM AUTHOR]

First described by Boissier and Simon in (Ther Recreat J 17:1225–1232, 1962), the hole-board has become a recognized test of anxiety and spatial memory. Benzodiazepines acting at the GABAA-BZD site increase hole-pokes in rats and mice, indicating a loss in behavioral inhibition concordant with the behavior of mutant mice deficient in the GABA transporter. Hole-poking also depends on arousal mechanisms dependent on dopaminergic transmission, as indicated by drug and null mutant studies. In addition, the behavior is modified in natural and null mutants affecting the cerebellum as well as null mutants affecting neuropeptides, growth factors, cell adhesion, and inflammation. Further research is required to determine convergences between genetic and pharmacological effects. [ABSTRACT FROM AUTHOR]

Chance discovery of spontaneous mutants with atrophy of the cerebellar cortex has unearthed genes involved in optimizing motor coordination. Rotorod, stationary beam, and suspended wire tests are useful in delineating behavioral phenotypes of spontaneous mutants with cerebellar atrophy such as Grid2Lc, Grid2ho, Rorasg, Agtpbp1pcd, Relnrl, and Dab1scm. Likewise, transgenic or null mutants serving as experimental models of spinocerebellar ataxia (SCA) are phenotyped with the same tests. Among experimental models of autosomal dominant SCA, rotorod deficits were reported in SCA1 to 3, SCA5 to 8, SCA14, SCA17, and SCA27 and stationary beam deficits in SCA1 to 3, SCA5, SCA6, SCA13, SCA17, and SCA27. Beam tests are sensitive to experimental therapies of various kinds including molecules affecting glutamate signaling, mesenchymal stem cells, anti-oligomer antibodies, lentiviral vectors carrying genes, interfering RNAs, or neurotrophic factors, and interbreeding with other mutants. [ABSTRACT FROM AUTHOR]

Several rodent models with spontaneous mutations causing cerebellar pathology are impaired in motor functions during the neonatal period, including Grid2 Lc , Rora sg , Dab1 scm , Girk2 Wv , Lmx1a dr-sst , Myo5a dn , Inpp4a wbl , and Cacna1a rol mice as well as shaker and dystonic rats. Deficits are also evident in murine null mutants such as Zic1 , Fgfr1 / FgFr2 , and Xpa / Ercc8 . Behavioral deficits are time-dependent following X-irradiated- or aspiration-induced lesions of the cerebellum in rats. In addition, motor functions are deficient after lesions in cerebellar-related pathways. As in animal subjects, sensorimotor disturbances have been described in children with cerebellar lesions. These results underline the importance of the cerebellum and its connections in the development of motor functions. [ABSTRACT FROM AUTHOR]

Two 5HT1A receptor agonists and chlordiazepoxide were examined in open-field, elevated plus maze, and emergence tests. At doses with no effect in the open-field, chlordiazepoxide increased open and open/total arm visits as well as open arm duration in the elevated plus maze, whereas 5HT1A receptor agonists showed an anxiolytic response on a single measure. The anxiolytic action of chlordiazepoxide was limited to the less active BALB/c strain. Unlike the 5HT1A receptor agonists, chlordiazepoxide was also anxiolytic in the emergence test, once again only in BALB/c and not C57BL/6J mice. Significant correlations were found between emergence latencies and specific indicators of anxiety in the elevated plus-maze in chlordiazepoxide-treated but not in mice treated with buspirone and 8-OH-DPAT. These results indicate that elevated plus-maze and emergence tests depend on benzodiazepine receptors. In contrast, 5HT1A receptor agonists were ineffective in the emergence test and no correlation was found between emergence latencies and specific indicators of anxiety in the elevated plus-maze. Though superficially similar, the emergence test seems to tap into a partially separate facet of anxiety. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial dysfunction and brain metabolic alteration are early neurofunctional aspects in Alzheimer''s disease (AD). Regional brain metabolism was analyzed by cytochrome c oxidase (COX) histochemistry in PS1-A246E mouse mutants, a model of autosomal dominant AD overexpressing beta-amyloid (Aβ) peptide without amyloidosis or cell degeneration. Immunohistochemical samples were analyzed on adjacent sections for regional Aβ1-42 levels, as well as DNA oxidative damage with 8-hydroxy-2-deoxyguanosine (8-OHdG). COX activity increased in the basal forebrain nuclear complex, specific parts of the amygdala and hippocampus, as well as in striatum and connected regions. On the contrary, a hypometabolism was observed in midline thalamic, interpeduncular, and pedonculopontine nuclei. The integration of these regions in circuitries subserving emotions, arousal, and cognitive functions may explain why neurochemical alterations in specific brain regions were linearly correlated with psychomotor slowing and disinhibition previously reported in the mutant. As the PS1-A246E model appears to mimick prodromal AD, the results support the existence of mitochondrial abnormalities prior to AD-related cognitive deficits. However, since affected PS1-A246E brain regions were not primarily those altered in AD-associated histopathological features and did not systematically display either Aβ overexpression or higher 8-OHdG immunolabelling, the hypermetabolism observed seems to comprise a compensatory reaction to early mitochondrial abnormalities; furthermore, neuronal synaptic function should be considered as particularly relevant in COX activity changes. [Copyright &y& Elsevier]

The function of the HERC1 gene has mainly been delineated by studying Herc1tbl (tambaleante) mutant mice, characterized by losses in cerebellar Purkinje cells, a lower number of synaptic vesicles in the hippocampus, and anomalies in climbing fiber projections from the inferior olive as well as alpha-motoneuron projections to the skeletal muscle. The salient behavioral phenotypes include cerebellar ataxia, a loss in motor coordination, muscle weakness, and spatial deficits. Similar neuropathological and behavioral profiles have been described in childhood-onset subjects with HERC1 variants, including cerebellar ataxia and hypotonia. [ABSTRACT FROM AUTHOR]

The dorsal immobility response (DIR) and the tonic immobility response (TIR) are cutaneo-motor reflexes typically triggered when a prey is seized. The neurochemical basis of the DIR appears to pass through the basal ganglia via dopaminergic fibers, while the neurochemical basis of the TIR appears to include a circuit comprising the amygdala, the periaqueductal gray (PAG), the dorsal raphe, and the nucleus magnus raphe (NMR) via glutamatergic, serotonergic, cholinergic, GABAergic, and opioid fibers. For the DIR, the basal ganglia also seem to be involved in regard to estradiol, while for the TIR, the HPA axis appears involved at the level of the amygdala and the oral pontine reticular nucleus. • The DIR requires the basal ganglia • The DIR depends on dopamine • The TIR requires the amygdala • The TIR requires the PAG • The TIR requires the depends on glutamate, serotonin • The TIR requires the depends on acetylcholine, GABA, opioids [ABSTRACT FROM AUTHOR]

The function of the Agtpbp1 gene has mainly been delineated by studying Agtpbp1 pcd (pcd) mutant mice, characterized by losses in cerebellar Purkinje and granule cells along with degeneration of retinal photoreceptors, mitral cells of the olfactory bulb, thalamic neurons, and alpha-motoneurons. As a result of cerebellar degeneration, cerebellar GABA and glutamate concentrations in Agtpbp1 pcd mutants decreased while monoamine concentrations increased. The salient behavioral phenotypes include cerebellar ataxia, a loss in motor coordination, and cognitive deficits. Similar neuropathogical and behavioral profiles have been described in childhood-onset human subjects with biallelic variants of AGTPBP1 , including cerebellar ataxia and hypotonia. [ABSTRACT FROM AUTHOR]

• Adult mouse displayed increased motor activity after postnatal corticosterone injections. • A better rotorod acquisition was obtained in adult mouse after postnatal corticosterone injections. • Postnatal corticosterone injections facilitated visomotor control in adult mouse. • Postnatal corticosterone injections altered cerebellar morphology in adult mouse. Glucocorticoids are involved in the developing brain but, in excessive amounts, may depress its growth and cause psychomotor development disorders. To test the long-term vulnerability of motor structures such as the cerebellum to supraphysiological corticosterone (CORT), the hormone was subcutaneously delivered at a dose of 20 mg/kg from postnatal day (P) 8 to P29 in C57BL/6 male mice evaluated for sensorimotor functions at P15, P22, P29, and 3 months. Relative to placebo, CORT increased motor activity in the open-field at P29 and 3 months as well as facilitating rotorod acquisition and visuomotor control necessary for swimming towards a visible goal without affecting spatial learning in the Morris water maze. CORT caused lobule-specific effects on cerebellar morphology by decreasing granule cell layer thickness in simplex lobule but increasing molecular and granule cell layer thickness in crus 2. The functional impact of these changes is indicated by significant correlations found between cerebellar size and activity levels or proficiency on the rotorod test of motor coordination. [ABSTRACT FROM AUTHOR]

Background: People with special needs have high unmet oral healthcare needs, partly because dentists find it difficult to access their oral cavity. The Oral Accessibility Spatula aims to improve oral accessibility. This prospective multicenter interventional open-label non-randomized patient-self-controlled trial assessed the ability of the spatula to improve the oral accessibility of special-needs patients during dental examinations. Methods: The cohort was a convenience sample of minor and adult patients with special needs due to physical, intellectual, and/or behavioral disorders who underwent dental check-up/treatment in five French tertiary hospitals/private clinics in 2016–2018 and evinced some (Venham-Score = 2–4) but not complete (Venham-Score = 5) resistance to oral examination. After inclusion, patients underwent oral examination without the spatula and then immediately thereafter oral examination with the spatula. Primary outcome was Oral Accessibility Score (0–12 points; higher scores indicate visualization and probing of the tooth sectors). Secondary outcomes were patient toleration (change in Venham-Score relative to first examination), safety, and Examiner Satisfaction Score (0–10; low scores indicate unsatisfactory examination). Results: The 201 patients were mostly non-elderly adults (18–64 years, 65%) but also included children (21%), adolescents (11%), and aged patients (3%). One-quarter, half, and one-quarter had Venham-Score = 2, 3, and 4 at inclusion, respectively. The spatula significantly improved Oral Accessibility Score (4.8 to 10.8), Venham-Score (3.1 to 2.6), and Examiner Satisfaction Score (3.4 to 7.2) (all p<0.001). There were no severe spatula-related adverse events. Conclusion: The spatula significantly improved oral access, was safe and well-tolerated by the patients, and markedly improved oral examination quality. [ABSTRACT FROM AUTHOR]

Receptors for glucocorticoid (GR) and corticotropin-releasing hormone (CRH) are largely found in brain sensorimotor structures, particularly in cerebellum, underlining a potential role of stress hormones in the regulation of motor function. Since CRH is involved in neuroplasticity, known for its trophic effect on synapses, we investigated how manipulations in corticosterone serum levels can modulate the CRH system in the cerebellum and affect motor coordination. Corticosterone at doses of either 15 or 30 mg/kg was injected in mice and the status of hormonal expression evaluated in cerebellum, hippocampus, and hypothalamus in undisturbed housing conditions or after different behavioral tests. Under both conditions, metabolic activity in numerous brain regions involved in motor functions and emotion was measured by means of cytochrome oxidase (COX) activity labeling. After six consecutive days of corticosterone administration, CRH-R1 transcription was downregulated in hypothalamic and cerebellar regions and hypometabolic changes were observed in mice treated with the higher dose for several limbic and sensorimotor circuitries, notably basal ganglia, deep cerebellar nuclei, and red nucleus. Corticosterone did not modify motor activity, anxiety, and spatial orientation, but decreased latencies before falling from the rotorod and prevented mice from reaching targets in the coat-hanger test. In addition, COX activities were similar to control mice except in ventromedial thalamus and dorsal neostriatum, possibly indicating that physical activity protected brain energy metabolism against the stress hormone. The present findings showed that the CRH/CRH-R1 system might play a role in mediating the effects of stress on cerebellar function, affecting especially motor learning tasks. [ABSTRACT FROM AUTHOR]

Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure induced by a ground-based model of spaceflight, hind limb unloading (HU), could affect B lymphopoiesis. To this end, we analyzed both bone parameters and the frequency of early hematopoietic precursors and cells of the B lineage after 3, 6,13, and 21 d of HU. We found that limb disuse leads to a decrease in both bone microstructure and the frequency of B-cell progenitors in the bone marrow. Although multipotent hematopoietic progenitors were not affected by HU, a decrease in B lymphopoiesis was observed as of the common lymphoid progenitor (CLP) stage with a major block at the progenitor B (pro-B) to precursor B (pre-B) cell transition (5- to 10-fold decrease). The modifications in B lymphopoiesis were similar to those observed in aged mice and, as with aging, decreased B-cell generation in HU mice was associated with reduced expression of B-cell transcription factors, early B-cell factor (EBF) and Pax5, and an alteration in STAT5-mediated IL-7 signaling. These findings demonstrate that mechanical unloading of hind limbs results in a decrease in early B-cell differentiation resembling age-related modifications in B lymphopoiesis. [ABSTRACT FROM AUTHOR]