Faculty Bibliography

This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high distress

PURPOSE: To develop a noncontrast magnetic resonance angiography (MRA) method for comprehensive evaluation of abdominopelvic arteries in a single 3D acquisition. MATERIALS AND METHODS: A noncontrast MRA (NC MRA) pulse sequence was developed using four inversion-recovery (IR) pulses and 3D balanced steady-state free precession (b-SSFP) readout to provide arterial imaging from renal to external iliac arteries. Respiratory triggered, high spatial resolution (1.3 x 1.3 x 1.7 mm(3) ) noncontrast angiograms were obtained in seven volunteers and ten patients referred for gadolinium-enhanced MRA (CE MRA). Images were assessed for diagnostic quality by two radiologists. Quantitative measurements of arterial signal contrast were also performed. RESULTS: NC MRA imaging was successfully completed in all subjects in 7.0 +/- 2.3 minutes. In controls, image quality of NC MRA averaged 2.79 +/- 0.39 on a scale of 0-3, where 3 is maximum. Image quality of NC MRA (2.65 +/- 0.41) was comparable to that of CE MRA (2.9 +/- 0.32) in all patients. Contrast ratio measurements in patients demonstrated that NC MRA provides arterial contrast comparable to source CE MRA images with adequate venous and excellent background tissue suppression. CONCLUSION: The proposed noncontrast MRA pulse sequence provides high-quality visualization of abdominopelvic arteries within clinically feasible scan times. J. Magn. Reson. Imaging 2011;33:1430-1439. (c) 2011 Wiley-Liss, Inc

During embryogenesis, the rhombic lip of the fourth ventricle is the germinal origin of a diverse collection of neuronal populations that ultimately reside in the brainstem and cerebellum. Rhombic lip neurogenesis requires the bHLH transcription factor Atoh1 (Math1), and commences shortly after neural tube closure (E9.5). Within the rhombomere 1 - isthmus region, the rhombic lip first produces brainstem and deep cerebellar neurons (E9.5-E12), followed by granule cell precursors after E12. While Atoh1 function is essential for all of these populations to be specified, the downstream genetic programs that confer specific properties to early and late born Atoh1 lineages are not well characterized. We have performed a comparative microarray analysis of gene expression within early and later born cohorts of Atoh1 expressing neural precursors purified from E14.5 embryos using a transgenic labeling strategy. We identify novel transcription factors, cell surface molecules, and cell cycle regulators within each pool of Atoh1 lineages that likely contribute to their distinct developmental trajectories and cell fates. In particular, our analysis reveals new insights into the genetic programs that regulate the specification and proliferation of granule cell precursors, the putative cell of origin for the majority of medulloblastomas

By application of the MRI method of diffusional kurtosis imaging, a substantially increased diffusional kurtosis was observed within the cerebral ischemic lesions of three stroke subjects, 13-26 h following the onset of symptoms. This increase is interpreted as probably reflecting a higher degree of diffusional heterogeneity in the lesions when compared with normal-appearing contralateral tissue. In addition, for two of the subjects with white matter infarcts, the increase had a strong fiber tract orientational dependence. It is proposed that this effect is consistent with a large drop in the intra-axonal diffusivity, possibly related to either axonal varicosities or alterations associated with the endoplasmic reticulum.

RATIONALE: Impulsivity is a vulnerability marker for drug addiction in which other behavioural traits such as anxiety and novelty seeking ('sensation seeking') are also widely present. However, inter-relationships between impulsivity, novelty seeking and anxiety traits are poorly understood. OBJECTIVE: The objective of this paper was to investigate the contribution of novelty seeking and anxiety traits to the expression of behavioural impulsivity in rats. METHODS: Rats were screened on the five-choice serial reaction time task (5-CSRTT) for spontaneously high impulsivity (SHI) and low impulsivity (SLI) and subsequently tested for novelty reactivity and preference, assessed by open-field locomotor activity (OF), novelty place preference (NPP), and novel object recognition (OR). Anxiety was assessed on the elevated plus maze (EPM) both prior to and following the administration of the anxiolytic drug diazepam, and by blood corticosterone levels following forced novelty exposure. Finally, the effects of diazepam on impulsivity and visual attention were assessed in SHI and SLI rats. RESULTS: SHI rats were significantly faster to enter an open arm on the EPM and exhibited preference for novelty in the OR and NPP tests, unlike SLI rats. However, there was no dimensional relationship between impulsivity and either novelty-seeking behaviour, anxiety levels, OF activity or novelty-induced changes in blood corticosterone levels. By contrast, diazepam (0.3-3 mg/kg), whilst not significantly increasing or decreasing impulsivity in SHI and SLI rats, did reduce the contrast in impulsivity between these two groups of animals. CONCLUSIONS: This investigation indicates that behavioural impulsivity in rats on the 5-CSRTT, which predicts vulnerability for cocaine addiction, is distinct from anxiety, novelty reactivity and novelty-induced stress responses, and thus has relevance for the aetiology of drug addiction.

This review critically examines progress in understanding the link between Alzheimer's disease (AD) molecular pathogenesis and behavior, with an emphasis on the impact of amyloid-beta. We present the argument that the AD research field requires more multifaceted analyses into the impacts of Alzheimer's pathogenesis which combine simultaneous molecular-, circuit-, and behavior-level approaches. Supporting this argument is a review of particular research utilizing similar, 'systems-level' methods in mouse models of AD. Related to this, a critique of common physiological and behavioral models is made-highlighting the likely usefulness of more refined and specific tools in understanding the relationship between candidate molecular pathologies and behavioral dysfunction. Finally, we propose challenges for future research which, if met, may greatly extend our current understanding of how AD molecular pathology impacts neural network function and behavior and possibly may lead to refinements in disease therapeutics

While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, 'Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation,' in this issue of Neuron

The local spatiotemporal pattern of light on the retina is often consistent with a single translational velocity which may also be interpreted as a superposition of spatial patterns translating with different velocities. Human perception reflects such interpretations, as can be demonstrated using stimuli constructed from a superposition of two drifting gratings. Depending on a variety of parameters, these stimuli may be perceived as a coherently moving plaid pattern or as two transparent gratings moving in different directions. Here, we propose a quantitative model that explains how and why such interpretations are selected. An observer's percept corresponds to the most probable interpretation of noisy measurements of local image motion, based on separate prior beliefs about the speed and singularity of visual motion. This model accounts for human perceptual interpretations across a broad range of angles and speeds. With optimized parameters, its components are consistent with previous results in motion perception