Faculty Bibliography

Sensorimotor coordination emerges early in development. The maturation period is characterized by the establishment of somatotopic cortical maps, the emergence of long-range cortical connections, heightened experience-dependent plasticity and spontaneous uncoordinated skeletal movement. How these various processes cooperate to allow the somatosensory system to form a three-dimensional representation of the body is not known. In the visual system, interactions between spontaneous network patterns and afferent activity have been suggested to be vital for normal development. Although several intrinsic cortical patterns of correlated neuronal activity have been described in developing somatosensory cortex in vitro, the in vivo patterns in the critical developmental period and the influence of physiological sensory inputs on these patterns remain unknown. We report here that in the intact somatosensory cortex of the newborn rat in vivo, spatially confined spindle bursts represent the first and only organized network pattern. The localized spindles are selectively triggered in a somatotopic manner by spontaneous muscle twitches, motor patterns analogous to human fetal movements. We suggest that the interaction between movement-triggered sensory feedback signals and self-organized spindle oscillations shapes the formation of cortical connections required for sensorimotor coordination

Using a multidisciplinary approach, we demonstrate that three different pathways are responsible for the transmission of rod signals across the mouse retina. Each pathway serves a primarily nonoverlapping range of stimulus intensities, with ganglion cells receiving either segregated or convergent inputs. For both on-center (ON) and off-center (OFF) ganglion cells, the primary rod pathway carries signals with the lowest threshold, whereas the secondary rod pathway is less sensitive by approximately 1 log unit. In addition, OFF signaling uses a tertiary rod pathway that is approximately 1 log unit less sensitive than the secondary. Although some ganglion cells received rod inputs exclusively from one of the pathways, others showed convergent inputs. Using pharmacological and genetic approaches, we defined classes of ON and OFF ganglion cells for which the scotopic inputs derive only from the primary pathway or from both primary and secondary pathways. In addition, we observed a class of OFF ganglion cell receiving mixed input from primary and tertiary pathways. Interestingly, OFF ganglion cells receiving convergent inputs from all three rod pathways or from the secondary and tertiary pathways together were never observed. Overall, our data show a complex arrangement of convergence and segregation of rod inputs to ganglion cells in the mammalian retina

BACKGROUND: Does the C. elegans nervous system contain multi-neuron computational modules that perform stereotypical functions? We attempt to answer this question by searching for recurring multi-neuron inter-connectivity patterns in the C. elegans nervous system's wiring diagram. RESULTS: Our statistical analysis reveals that some inter-connectivity patterns containing two, three and four (but not five) neurons are significantly over-represented relative to the expectations based on the statistics of smaller inter-connectivity patterns. CONCLUSIONS: Over-represented patterns (or motifs) are candidates for computational modules that may perform stereotypical functions in the C. elegans nervous system. These modules may appear in other species and need to be investigated further.

The question of whether or not the locus coeruleus (LC) participates in the control of motor activity has been controversial due to difficulties in demonstrating permanent motor deficits after neurotoxic lesions of this nucleus or of the dorsal noradrenergic bundle (DNB). In the present experiments it was shown in rats that acute local blockade (with terazosin) or stimulation (with phenylephrine) of LC alpha(1)-adrenoceptors respectively blocked or stimulated exploratory behavior in a novel cage and the home cage. Moreover, previous lesion of the DNB by i.p. DSP4 abolished the behavioral changes to local LC alpha(1)-receptor manipulation but did not affect motor activity in the novel or home cage by itself. These findings are consistent with the hypothesis that the intact LC does contribute to motor activity control, exerted in part by its alpha(1)-receptors; however, the permanent loss of this nucleus is compensated for by remaining CNS motor structures

Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels

We quantitatively studied the ontogeny of oculomotor behavior in larval fish as a foundation for studies linking oculomotor structure and function with genetics. Horizontal optokinetic and vestibuloocular reflexes (OKR and VOR, respectively) were measured in three different species (goldfish, zebrafish, and medaka) during the first month after hatching. For all sizes of medaka, and most zebrafish, Bode plots of OKR (0.065-3.0 Hz, +/-10 degrees/s) revealed that eye velocity closely followed stimulus velocity (gain > 0.8) at low frequency but dropped sharply above 1 Hz (gain < 0.3 at 3 Hz). Goldfish showed increased gain proportional to size across frequencies. Linearity testing with steps and sinusoids showed excellent visual performance (gain > 0.8) in medaka almost from hatching; but zebrafish and goldfish exhibited progressive improvement, with only the largest equaling medaka performance. Monocular visual stimulation in zebrafish and goldfish produced gains of 0.5 versus <0.1 for the eye viewing a moving versus stationary stimulus pattern but 0.25 versus <0.1 in medaka. Angular VOR appeared much later than OKR, initially at only high accelerations (>200 degrees /s at 0.5 Hz), first in medaka followed by larger (8.11 mm) zebrafish; but it was virtually nonexistent in goldfish. Velocity storage was not observed except for an eye velocity build-up in the largest medaka. In summary, a robust OKR was achieved shortly after hatching in all three species. In contrast, larval fish seem to be unique among vertebrates tested in their lack of significant angular VOR at stages where active movement is required for feeding and survival

The AII amacrine cells are critical elements in the primary rod pathway of the mammalian retina, acting as an obligatory conduit of rod signals to both on- and off-center ganglion cells. In addition to the chemical synaptic circuitry they subserve, AII cells form two types of electrical synapses corresponding to gap junctions formed between neighboring AII cells as well as junctions formed between AII cells and on-center cone bipolar cells. Our recent results indicate that coupling between AII cells and cone bipolar cells forms an obligatory synapse for transmission of scotopic visual signals to on-center ganglion cells. In contrast, AII-AII cell coupling acts to maintain the sensitivity of the primary rod pathway by allowing for summation of synchronous activity and the attenuation of asynchronous background noise. Further, the conductance of AII-AII cell gap junctions is highly dynamic, regulated by ambient light conditions, thereby preserving the fidelity of rod signaling over the scotopic operating range from starlight to twilight