Faculty Bibliography

Although cerebellar Purkinje cell complex spikes occur at low frequency (approximately 1/s), each complex spike is often associated with a high-frequency burst (approximately 500/s) of climbing fiber spikes. We examined the possibility that signals are present within the climbing fiber bursts. By intracellularly recording from depolarized, nonspiking Purkinje cells in anesthetized pigmented rabbits, climbing fiber burst patterns were investigated by determining the number of components in the induced compound EPSPs during spontaneous activity and during visual stimulation. For our sample of 43 cells, >70% of all EPSPs were of the compound type composed of two or three EPSPs. During spontaneous activity, the number of components in each compound EPSP was not related to the latency to the succeeding compound EPSP. Conversely, the number of components in each compound EPSP was related to its latency after the preceding compound EPSP. This latency increased from 0.62 s for one-component EPSPs to 1.69 s for compound EPSPs with four or more components. The effect of visual stimulation on the climbing fiber activity was studied in 19 floccular Purkinje cells whose low-frequency interburst climbing fiber response was modulated by movement about the vertical axis. During sinusoidal oscillation (0.1 Hz, +/-10 degrees), compound EPSPs with a larger number of components tended to be more prevalent during movement in the excitatory direction than in the inhibitory direction. Thus, climbing fibers can, in addition to modulation of their low interburst frequency, transmit signals in the form of the number of spikes within each high-frequency burst

Sensory signals of widely differing dynamic range and intensity are transformed into a common firing rate code by thalamocortical neurons. While a great deal is known about the ionic currents, far less is known about the specific channel subtypes regulating thalamic firing rates. We hypothesized that different K(+) and Ca(2+) channel subtypes control different stimulus-response curve properties. To define the channels, we measured firing rate while pharmacologically or genetically modulating specific channel subtypes. Inhibiting Kv3.2 K(+) channels strongly suppressed maximum firing rate by impairing membrane potential repolarization, while playing no role in the firing response to threshold stimuli. By contrast, inhibiting Kv1 channels with alpha-dendrotoxin or maurotoxin strongly increased firing rates to threshold stimuli by reducing the membrane potential where action potentials fire (V(th)). Inhibiting SK Ca(2+)-activated K(+) channels with apamin robustly increased gain (slope of the stimulus-response curve) and maximum firing rate, with minimum effects on threshold responses. Inhibiting N-type Ca(2+) channels with omega-conotoxin GVIA or omega-conotoxin MVIIC partially mimicked apamin, while inhibiting L-type and P/Q-type Ca(2+) channels had small or no effects. EPSC-like current injections closely mimicked the results from tonic currents. Our results show that Kv3.2, Kv1, SK potassium and N-type calcium channels strongly regulate thalamic relay neuron sensory transmission and that each channel subtype controls a different stimulus-response curve property. Differential regulation of threshold, gain and maximum firing rate may help vary the stimulus-response properties across and within thalamic nuclei, normalize responses to diverse sensory inputs, and underlie sensory perception disorders

Cajal-Retzius (CR) cells, the earliest-born neurons in the neocortex, arise from discrete sources within the telencephalon, including the dorsal midline and the pallial-subpallial boundary (PSB). In particular, the cortical hem, a region of high bone morphogenetic proteins (BMPs) and Wnt (wingless-type MMTV integration site family) expression but lacking in Foxg1 (forkhead box G1) is a major source of CR neurons. Whether CR cells from distinct origins arise from disparate developmental processes or share a common mechanism is unclear. To elucidate the molecular basis of CR cell development, we assessed the role of both Foxg1 and dorsal midline signaling in the production of cortical hem- and PSB-derived CR cells. We demonstrate that the loss of Foxg1 results in the overproduction of both of these CR populations. However, removal of Foxg1 at embryonic day 13, although expanding the number of CR cells with a PSB phenotype, does not result in an expansion of BMPs or Wnts in the dorsomedial signaling center. Conversely, loss of the dorsal midline ligands as observed in Gli3 (glioma-associated oncogene homolog 3) mutants results in the loss of the cortical hem-derived CR character but does not affect the specification of PSB-derived CR cells. Hence, our findings demonstrate that, although the specification of cortical hem-derived CR cells is dependent on signaling from the dorsal midline, Foxg1 functions to repress the generation of both cortical hem- and PSB-derived CR cells

The visual system, with its ability to perceive motion, is crucial for most animals to walk or fly steadily. Theoretical models of motion detection exist, but the underlying cellular mechanisms are still poorly understood. In this issue of Neuron, Rister and colleagues dissect the function of neuronal subtypes in the optic lobe of Drosophila to reveal their role in motion detection.

Phosphodiesterase type 5 (PDE5) acts specifically on cyclic guanosine monophosphate (cGMP) and terminates cGMP-mediated signalling. PDE5 has a well established role in vascular smooth muscle, where specific inhibitors of PDE5 such as sildenafil correct erectile dysfunction by augmenting cGMP-mediated vascular relaxation. However, the role of PDE5 outside of the vasculature has received little attention. The present study tested PDE5 inhibitors on the cGMP-mediated modulation of K(+) channels in the neurohypophysis (posterior pituitary). Photolysis of caged-cGMP enhanced current through Ca(2+)-activated K(+) channels, and this enhancement recovered in about 2 min. Sildenafil essentially eliminated this recovery, suggesting that the reversal of K(+) current enhancement depends on cGMP breakdown. Activation of nitric oxide synthase during trains of activity in pituitary nerve terminals enhances excitability. When trains of stimulation were applied at regular intervals, sildenafil enhanced the excitability of neurohypophysial nerve terminals and increased the action potential firing probability. T-1032, a compound with high specificity for PDE5 over PDE6, had a similar action. Voltage imaging in intact neurohypophysis with a voltage sensitive absorbance dye showed that T-1032 reduced the failure of propagating action potentials during trains of activity. This indicates that PDE5 activity limits action potential propagation in neurohypophysial axons. Immunoassay of oxytocin, a neuropeptide hormone secreted by the posterior pituitary, demonstrated that sildenafil increased electrically evoked release. Thus, PDE5 plays an important role in the regulation of neurohypophysial function, and blockade of this enzyme can enhance the use-dependent facilitation of neurohypophysial secretion

OBJECTIVE: Although most mild traumatic brain injury (mTBI) patients suffer any of several post-concussion symptoms suggestive of thalamic involvement, they rarely present with any MRI-visible pathology. The aim here, therefore, is to characterize their thalamic metabolite levels with proton MR spectroscopy (1H-MRS) compared with healthy controls. METHODS: T1-weighted MRI and multi-voxel 1H-MRS were acquired at 3 Tesla from 20 mTBI (Glasgow Coma Scale score of 15-13) patients, 19-59 years old, 0-7 years post-injury; and from 17 age and gender matched healthy controls. Mixed model regression was used to compare patients and controls with respect to the mean absolute N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) levels within each thalamus. RESULTS: The mTBI-induced thalamic metabolite concentration changes were under +/- 13.0% for NAA, +/- 13.5% for Cr and +/- 18.8% for Cho relative to their corresponding concentrations in the controls: NAA: 10.08 +/- 0.30 (mean +/- standard error), Cr: 5.62 +/- 0.18 and Cho: 2.08 +/- 0.09 mM. These limits represent the minimal detectable differences between the two cohorts. CONCLUSION: The change in metabolic levels in the thalamus of patients who sustained clinically defined mTBI could be an instrumental characteristic of 'mildness'. 1H-MRS could, therefore, serve as an objective laboratory indicator for differentiating 'mild' from more severe categories of head-trauma, regardless of the presence or lack of current clinical symptoms

BACKGROUND AND PURPOSE: Deposition of iron has been recognized recently as an important factor of pathophysiologic change including neurodegenerative processes in multiple sclerosis (MS). We propose that there is an excess accumulation of iron in the deep gray matter in patients with MS that can be measured with a newly developed quantitative MR technique--magnetic field correlation (MFC) imaging. MATERIALS AND METHODS: With a 3T MR system, we studied 17 patients with relapsing-remitting MS and 14 age-matched healthy control subjects. We acquired MFC imaging using an asymmetric single-shot echo-planar imaging sequence. Regions of interest were selected in both deep gray matter and white matter regions, and the mean MFC values were compared between patients and controls. We also correlated the MFC data with lesion load and neuropsychologic tests in the patients. RESULTS: MFC measured in the deep gray matter in patients with MS was significantly higher than that in the healthy controls (P < or = .03), with an average increase of 24% in the globus pallidus, 39.5% in the putamen, and 30.6% in the thalamus. The increased iron deposition measured with MFC in the deep gray matter in the patients correlated positively with the total number of MS lesions (thalamus: r = 0.61, P = .01; globus pallidus: r = 0.52, P = .02). A moderate but significant correlation between the MFC value in the deep gray matter and the neuropsychologic tests was also found. CONCLUSION: Quantitative measurements of iron content with MFC demonstrate increased accumulation of iron in the deep gray matter in patients with MS, which may be associated with the disrupted iron outflow pathway by lesions. Such abnormal accumulation of iron may contribute to neuropsychologic impairment and have implications for neurodegenerative processes in MS

The occipital cortex, normally visual, can be activated by auditory or somatosensory tasks in the blind. This cross-modal compensation appears after early or late onset of blindness with differences in activation between early and late blind. This could support the hypothesis of a reorganization of sensory pathways in the early blind that does not occur in later onset blindness. Using immunohistochemistry of the c-Fos protein following a white noise stimulus and injections of the anterograde tracer dextran-biotin in the inferior colliculus, we studied how the occurrence of blindness influences cross-modal compensation in the mutant anophthalmic mouse strain and in C57BL/6 mice enucleated at birth. We observed, in mutant mice, immunolabeled nuclei in the visual thalamus - the dorsal lateral geniculate nucleus - in the primary visual area (V1) and a few labeled nuclei in the secondary visual area (V2). In enucleated mice, we observed auditory activity mainly in V2 but also sparsely in V1. No labeled cells could be found in the visual thalamus. Tracing studies confirmed the difference between anophthalmic and birth-enucleated mice: whereas the first group showed inferior colliculus projections entering both the dorsal lateral geniculate and the latero-posterior nuclei, in the second, auditory fibers were found only within the latero-posterior thalamic nucleus. None was found in controls with intact eyes. We suggest that the prenatal period of spontaneous retinal activity shapes the differences of the sensory reorganization in mice.

We report that temporal spike sequences from hippocampal place neurons of rats on an elevated track recurred in reverse order at the end of a run, but in forward order in anticipation of the run, coinciding with sharp waves. Vector distances between the place fields were reflected in the temporal structure of these sequences. This bidirectional re-enactment of temporal sequences may contribute to the establishment of higher-order associations in episodic memory