Faculty Bibliography

Odor perception is hypothesized to be an experience-dependent process involving the encoding of odor objects by distributed olfactory cortical ensembles. Olfactory cortical neurons coactivated by a specific pattern of odorant evoked input become linked through association fiber synaptic plasticity, creating a template of the familiar odor. In this way, experience and memory play an important role in odor perception and discrimination. In other systems, memory consolidation occurs partially via slow-wave sleep (SWS)-dependent replay of activity patterns originally evoked during waking. SWS is ideal for replay given hyporesponsive sensory systems, and thus reduced interference. Here, using artificial patterns of olfactory bulb stimulation in a fear conditioning procedure in the rat, we tested the effects of imposed post-training replay during SWS and waking on strength and precision of pattern memory. The results show that imposed replay during post-training SWS enhanced the subsequent strength of memory, whereas the identical replay during waking induced extinction. The magnitude of this enhancement was dependent on the timing of imposed replay relative to cortical sharp-waves. Imposed SWS replay of stimuli, which differed from the conditioned stimulus, did not affect conditioned stimulus memory strength but induced generalization of the fear memory to novel artificial patterns. Finally, post-training disruption of piriform cortex intracortical association fiber synapses, hypothesized to be critical for experience-dependent odor coding, also impaired subsequent memory precision but not strength. These results suggest that SWS replay in the olfactory cortex enhances memory consolidation, and that memory precision is dependent on the fidelity of that replay.

Established as a method to study anatomic changes, such as renal tumors or atherosclerotic vascular disease, magnetic resonance imaging (MRI) to interrogate renal function has only recently begun to come of age. In this review, we briefly introduce some of the most important MRI techniques for renal functional imaging, and then review current findings on their use for diagnosis and monitoring of major kidney diseases. Specific applications include renovascular disease, diabetic nephropathy, renal transplants, renal masses, acute kidney injury, and pediatric anomalies. With this review, we hope to encourage more collaboration between nephrologists and radiologists to accelerate the development and application of modern MRI tools in nephrology clinics.

Genome-wide association studies (GWAS) have implicated SCN10A, which encodes a nociceptor-associated voltage-gated sodium channel subunit, as a modulator of cardiac conduction; however, this role has traditionally been ascribed to SCN5A, which is highly expressed in cardiac muscle. SCN10A is believed to affect cardiac conduction either directly through cardiomyocytes or indirectly via intracardiac neurons. In this issue of the JCI, van den Boogaard and colleagues introduce a third possibility: that the SCN10A locus acts as an enhancer of SCN5A gene expression. The authors demonstrate that SCN10A expression is negligible within human and murine hearts, and that a T-box enhancer within the SCN10A locus drives SCN5A expression within cardiomyocytes. This work reasserts SCN5A as the key determinant of cardiac conduction and highlights the importance of deciphering the functionality of coding versus noncoding regions when interpreting GWAS data.

Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer's disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Although DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age-related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3-7.5 months of age. Ts65Dn dams were maintained on a choline-supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; post weaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, and brains were sectioned and immunolabeled for choline acetyltransferase (ChAT) or p75-neurotrophin receptor (p75(NTR) ). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn-unsupplemented mice displayed region- and immunolabel-dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal-diet choline supplementation attenuates some of the genotype-dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. J. Comp. Neurol. 522:1390-1410, 2014. (c) 2013 Wiley Periodicals, Inc.

Accurate assessment of blood volume (BV) may be helpful for prescribing hemodialysis (HD) and for reducing complications related to hypovolemia and volume overload. Monitoring changes in relative BV (RBV) using hematocrit, e.g., Crit-Line Monitor (CLM-III), an indirect method, cannot be used to determine absolute BV. We report the first study of BV measurement for assessing volume status in HD patients using the indicator dilutional method. Ten adult HD patients were enrolled in this prospective observational study. BV measurement was performed before and after HD using BV analysis (BVA)-100 (Daxor Corporation, New York, NY, USA). BVA-100 calculates BV using radiolabeled albumin (Iodine-131) followed by serial measures of the radioisotope. Fluid loss from the extravascular space was calculated by subtracting the change in BV from total weight loss. Intradialytic changes in RBV were measured by CLM-III. Eight out of 10 cases had significant hypervolemia, two cases were normovolemic. The range of BV variation from predicted normal was 156 to 1990 mL. Significant inter-individual differences in extravascular space fluid loss ranged from 54% to 99% of total weight loss. Spearman correlation showed a good correlation in the measurement of RBV by BVA-100 and CLM-III in 8 out of 10 patients (r(2) = 0.64). BV measurement using BVA-100 is useful to determine absolute BV as well as changes in BV and correlates reasonably well with CLM-III measurements. Individual refilling ability can be determined as well. This may prove useful in prescribing and monitoring ultrafiltration rates, establishment of optimal BV in HD patients and reducing morbidity and mortality associated with chronic HD.

Abstract Background: Lymphedema (LE) is a frequent complication following breast cancer treatment. While progress is being made in the identification of phenotypic risk factors for the development of LE, little information is available on the molecular characterization of LE. The purpose of this study was to determine if variations in pro- and anti-inflammatory cytokine genes were associated with LE following breast cancer treatment. Methods and Results: Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n=155) and without LE (n=387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease, and a higher number of lymph nodes removed. Genetic associations were identified for three genes (i.e., interleukin (IL4) 4 (rs2227284), IL 10 (rs1518111), and nuclear kappa factor beta 2 (NFKB2 (rs1056890)) associated with inflammatory responses. Conclusions: These genetic associations suggest a role for a number of pro- and anti-inflammatory genes in the development of LE following breast cancer treatment.

BACKGROUND: Cancer pain severely limits function and significantly reduces quality of life. Subtypes of sensory neurons involved in cancer pain and proliferation are not clear. METHODS: We produced a cancer model by inoculating human oral squamous cell carcinoma (SCC) cells into the hind paw of athymic mice. We quantified mechanical and thermal nociception using the paw withdrawal assays. Neurotoxins isolectin B4-saporin (IB4-SAP), or capsaicin was injected intrathecally to selectively ablate IB4(+) neurons or TRPV1(+) neurons, respectively. JNJ-17203212, a TRPV1 antagonist, was also injected intrathecally. TRPV1 protein expression in the spinal cord was quantified with western blot. Paw volume was measured by a plethysmometer and was used as an index for tumor size. Ki-67 immunostaining in mouse paw sections was performed to evaluate cancer proliferation in situ. RESULTS: We showed that mice with SCC exhibited both mechanical and thermal hypersensitivity. Selective ablation of IB4(+) neurons by IB4-SAP decreased mechanical allodynia in mice with SCC. Selective ablation of TRPV1(+) neurons by intrathecal capsaicin injection, or TRPV1 antagonism by JNJ-17203212 in the IB4-SAP treated mice completely reversed SCC-induced thermal hyperalgesia, without affecting mechanical allodynia. Furthermore, TRPV1 protein expression was increased in the spinal cord of SCC mice compared to normal mice. Neither removal of IB4(+) or TRPV1(+) neurons affected SCC proliferation. CONCLUSIONS: We show in a mouse model that IB4(+) neurons play an important role in cancer-induced mechanical allodynia, while TRPV1 mediates cancer-induced thermal hyperalgesia. Characterization of the sensory fiber subtypes responsible for cancer pain could lead to the development of targeted therapeutics.

BACKGROUND AND PURPOSE: Diffusional kurtosis imaging is an extension of DTI but includes non-Gaussian diffusion effects, allowing more comprehensive characterization of microstructural changes during brain development. Our purpose was to use diffusional kurtosis imaging to measure age-related microstructural changes in both the WM and GM of the developing human brain. MATERIALS AND METHODS: Diffusional kurtosis imaging was performed in 59 subjects ranging from birth to 4 years 7 months of age. Diffusion metrics, fractional anisotropy, and mean kurtosis were collected from VOIs within multiple WM and GM structures and subsequently analyzed with respect to age. Diffusional kurtosis tractography images at various stages of development were also generated. RESULTS: Fractional anisotropy and mean kurtosis both showed age-related increases in all WM regions, reflecting progression of diffusional anisotropy throughout development, predominantly in the first 2 years of life (eg, 70% and 157% increase in fractional anisotropy and mean kurtosis, respectively, from birth to 2 years for the splenium). However, mean kurtosis detected continued microstructural changes in WM past the fractional anisotropy plateau, accounting for more delayed isotropic changes (eg, 90% of maximum fractional anisotropy was reached at 5 months, whereas 90% of maximum mean kurtosis occurred at 18 months for the external capsule). Mean kurtosis may also provide greater characterization of GM maturation (eg, the putamen showed no change in fractional anisotropy but an 81% change in mean kurtosis from birth to 4 years 7 months). CONCLUSIONS: Mean kurtosis detects significant microstructural changes consistent with known patterns of brain maturation. In comparison with fractional anisotropy, mean kurtosis may offer a more comprehensive evaluation of age-related microstructural changes in both WM and GM and is potentially a valuable technique for studying brain development.