Faculty Bibliography

BACKGROUND: Hereditary sensory and autonomic neuropathy type III features marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. METHODS: Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26 of 30. RESULTS: Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7 degrees +/- 1.0 degrees , and the range was very wide (2.8 degrees -18.1 degrees ); conversely, absolute error was only 2.7 degrees +/- 0.3 degrees (1.6 degrees -5.5 degrees ) in the controls and 3.0 degrees +/- 0.2 degrees (2.1 degrees -3.4 degrees ) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients. CONCLUSIONS: These results suggest that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III.

Granule cells (GCs) of the dentate gyrus (DG) are considered to be quiescent-they rarely fire action potentials. In contrast, the other glutamatergic cell type in the DG, hilar mossy cells (MCs) often have a high level of spontaneous activity based on recordings in hippocampal slices. MCs project to GCs, so activity in MCs could play an important role in activating GCs. Therefore, we investigated whether MCs were active under basal conditions in vivo, using the immediate early gene c-fos as a tool. We hypothesized that MCs would exhibit c-fos expression even if rats were examined randomly, under normal housing conditions. Therefore, adult male rats were perfused shortly after removal from their home cage and transfer to the laboratory. Remarkably, most c-fos immunoreactivity (ir) was in the hilus, especially temporal hippocampus. C-fos-ir hilar cells co-expressed GluR2/3, suggesting that they were MCs. C-fos-ir MCs were robust even when the animal was habituated to the investigator and laboratory where they were euthanized. However, c-fos-ir in dorsal MCs was reduced under these circumstances, suggesting that ventral and dorsal MCs are functionally distinct. Interestingly, there was an inverse relationship between MC and GC layer c-fos expression, with little c-fos expression in the GC layer in ventral sections where MC expression was strong, and the opposite in dorsal hippocampus. The results support the hypothesis that a subset of hilar MCs are spontaneously active in vivo and provide other DG neurons with tonic depolarizing input. (c) 2013 Wiley Periodicals, Inc.

The tubulin heterodimer consists of one alpha- and one beta-tubulin polypeptide. Neither protein can partition to the native state or assemble into polymerization competent heterodimers without the concerted action of a series of chaperone proteins including five tubulin-specific chaperones (TBCs) termed TBCA-TBCE. TBCA and TBCB bind to and stabilize newly synthesized quasi-native beta- and alpha-tubulin polypeptides, respectively, following their generation via multiple rounds of ATP-dependent interaction with the cytosolic chaperonin. There is free exchange of beta-tubulin between TBCA and TBCD, and of alpha-tubulin between TBCB and TBCE, resulting in the formation of TBCD/beta and TBCE/alpha, respectively. The latter two complexes interact, forming a supercomplex (TBCE/alpha/TBCD/beta). Discharge of the native alpha/beta heterodimer occurs via interaction of the supercomplex with TBCC, which results in the triggering of TBC-bound beta-tubulin (E-site) GTP hydrolysis. This reaction acts as a switch for disassembly of the supercomplex and the release of E-site GDP-bound heterodimer, which becomes polymerization competent following spontaneous exchange with GTP. The tubulin-specific chaperones thus function together as a tubulin assembly machine, marrying the alpha- and beta-tubulin subunits into a tightly associated heterodimer. The existence of this evolutionarily conserved pathway explains why it has never proved possible to isolate alpha- or beta-tubulin as stable independent entities in the absence of their cognate partners, and implies that each exists and is maintained in the heterodimer in a nonminimal energy state. Here, we describe methods for the purification of recombinant TBCs as biologically active proteins following their expression in a variety of host/vector systems.

BACKGROUND AND PURPOSE: CC is extensively involved in MS with interhemispheric dysfunction. The purpose of this study was to determine whether interhemispheric correlation is altered in MS by use of a recently developed RS-fMRI homotopy technique and whether these homotopic changes correlate with CC pathology. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting MS and 24 age-matched healthy volunteers were studied with RS-fMRI and DTI acquired at 3T. The Pearson correlation of each pair of symmetric interhemispheric voxels of RS-fMRI time-series data was performed to compute VMHC, and z-transformed for subsequent group-level analysis. In addition, 5 CC segments in the midsagittal area and DTI-derived FA were measured to quantify interhemispheric microstructural changes and correlate with global and regional VMHC in MS. RESULTS: Relative to control participants, patients with MS exhibited an abnormal homotopic pattern with decreased VMHC in the primary visual, somatosensory, and motor cortices and increased VMHC in several regions associated with sensory processing and motor control including the insula, thalamus, pallidum, and cerebellum. The global VMHC correlates moderately with the average FA of the entire CC for all participants in both groups (r = 0.3; P = .03). CONCLUSIONS: Our data provide preliminary evidence of the potential usefulness of VMHC analyses for the detection of abnormalities of interhemispheric coordination in MS. We demonstrated that the whole-brain homotopic RS-fMRI pattern was altered in patients with MS, which was partially associated with the underlying structural degenerative changes of CC measured with FA.

OBJECTIVE: To determine if carbidopa, a dopa-decarboxylase inhibitor that blocks the formation of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD). BACKGROUND: Patients with FD, an hereditary neuropathy that affects the development of sensory neurons of the baroreflex, are unable to restrain the release of catecholamines from sympathetic nerve terminals at times of stress. Recurrent attacks of nausea, retching and vomiting, associated with high levels of circulating dopamine are a disabling feature of the disease for which there is no effective treatment. DESIGN/METHODS: We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa, an inhibitor of the enzyme dopa decarboxylase that does not cross the blood brain barrier. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy. RESULTS: All patients experienced severe cyclical nausea and uncontrollable retching that was refractory to standard treatments. Carbidopa at an average daily dose of 480 mg (range 325 to 600 mg/day) was well tolerated. In the double-blind phase, patients experienced significantly less nausea and retching while on carbidopa than on placebo (p<0.03 and p<0.02. respectively). Twenty-four hour urinary dopamine excretion was significantly lower while on carbidopa (147+/-32 ug/g crt) than while on placebo (222+/-41 ug/g crt, p<0.05). CONCLUSIONS: Carbidopa appears to be a safe and effective antiemetic in patients with FD likely by reducing the formation of dopamine outside the brain. Larger trials are warranted

Neurons throughout the brain show spike activity that is temporally correlated to that expressed by their neighbors, yet the generating mechanism(s) remains unclear. In the retina, ganglion cells (GCs) show robust, concerted spiking that shapes the information transmitted to central targets. Here we report the synaptic circuits responsible for generating the different types of concerted spiking of GC neighbors in the mouse retina. The most precise concerted spiking was generated by reciprocal electrical coupling of GC neighbors via gap junctions, whereas indirect electrical coupling to a common cohort of amacrine cells generated the correlated activity with medium precision. In contrast, the correlated spiking with the lowest temporal precision was produced by shared synaptic inputs carrying photoreceptor noise. Overall, our results demonstrate that different synaptic circuits generate the discrete types of GC correlated activity. Moreover, our findings expand our understanding of the roles of gap junctions in the retina, showing that they are essential for generating all forms of concerted GC activity transmitted to central brain targets.

BACKGROUND: The present study (1) characterizes a physiologic phenotype of restrictive dysfunction due to airway injury and (2) compares this phenotype to the phenotype of interstitial lung disease (ILD). METHODS: This is a retrospective study of 54 persistently symptomatic subjects following World Trade Center (WTC) dust exposure. Inclusion criteria were reduced vital capacity (VC), FEV1/VC > 77%, and normal chest roentgenogram. Measurements included spirometry, plethysmography, diffusing capacity of lung for carbon monoxide (Dlco), impulse oscillometry (IOS), inspiratory/expiratory CT scan, and lung compliance (n = 16). RESULTS: VC was reduced (46% to 83% predicted) because of the reduction of expiratory reserve volume (43% +/- 26% predicted) with preservation of inspiratory capacity (IC) (85% +/- 16% predicted). Total lung capacity (TLC) was reduced, confirming restriction (73% +/- 8% predicted); however, elevated residual volume to TLC ratio (0.35 +/- 0.08) suggested air trapping (AT). Dlco was reduced (78% +/- 15% predicted) with elevated Dlco/alveolar volume (5.3 +/- 0.8 [mL/mm Hg/min]/L). IOS demonstrated abnormalities in resistance and/or reactance in 50 of 54 subjects. CT scan demonstrated bronchial wall thickening and/or AT in 40 of 54 subjects; parenchymal disease was not evident in any subject. Specific compliance at functional residual capacity (FRC) (0.07 +/- 0.02 [L/cm H2O]/L) and recoil pressure (Pel) at TLC (27 +/- 7 cm H2O) were normal. In contrast to patients with ILD, lung expansion was not limited, since IC, Pel, and inspiratory muscle pressure were normal. Reduced TLC was attributable to reduced FRC, compatible with airway closure in the tidal range. CONCLUSIONS: This study describes a distinct physiologic phenotype of restriction due to airway dysfunction. This pattern was observed following WTC dust exposure, has been reported in other clinical settings (eg, asthma), and should be incorporated into the definition of restrictive dysfunction.

Neuromodulatory control by oxytocin is essential to a wide range of social, parental and stress-related behaviours. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels and with genetic alterations of the oxytocin receptor (OXTR). Thirty years ago, Muhlethaler et al. found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here we describe in mammalian hippocampus a simple yet powerful mechanism by which oxytocin enhances cortical information transfer while simultaneously lowering background activity, thus greatly improving the signal-to-noise ratio. Increased fast-spiking interneuron activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the fast-spiking interneuron-pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. We show the generality of this novel circuit mechanism by activation of fast-spiking interneurons with cholecystokinin or channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision.

Neurobiological correlates of adaptation to spectrally degraded speech were investigated with fMRI before and after exposure to a portable real-time speech processor that implements an acoustic simulation model of a cochlear implant (CI). The speech processor, in conjunction with isolating insert earphones and a microphone to capture environment sounds, was worn by participants over a two week chronic exposure period. fMRI and behavioral speech comprehension testing were conducted before and after this two week period. After using the simulator each day for 2h, participants significantly improved in word and sentence recognition scores. fMRI shows that these improvements came accompanied by changes in patterns of neuronal activation. In particular, we found additional recruitment of visual, motor, and working memory areas after the perceptual training period. These findings suggest that the human brain is able to adapt in a short period of time to a degraded auditory signal under a natural learning environment, and gives insight on how a CI might interact with the central nervous system. This paradigm can be furthered to investigate neural correlates of new rehabilitation, training, and signal processing strategies non-invasively in normal hearing listeners to improve CI patient outcomes.