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1.  Mutation of Npr2 Leads to Blurred Tonotopic Organization of Central Auditory Circuits in Mice 
PLoS Genetics  2014;10(12):e1004823.
Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reaching the brainstem, SGN axons bifurcate in a stereotyped pattern, innervating target neurons in the anteroventral cochlear nucleus (aVCN) with one branch and in the posteroventral and dorsal cochlear nuclei (pVCN and DCN) with the other. Each branch is tonotopically organized, thereby distributing acoustic information systematically along multiple parallel pathways for processing in the brainstem. In mice with a mutation in the receptor guanylyl cyclase Npr2, this spatial organization is disrupted. Peripheral SGN processes appear normal, but central SGN processes fail to bifurcate and are disorganized as they exit the auditory nerve. Within the cochlear nuclei, the tonotopic organization of the SGN terminal arbors is blurred and the aVCN is underinnervated with a reduced convergence of SGN inputs onto target neurons. The tonotopy of circuitry within the cochlear nuclei is also degraded, as revealed by changes in the topographic mapping of tuberculoventral cell projections from DCN to VCN. Nonetheless, Npr2 mutant SGN axons are able to transmit acoustic information with normal sensitivity and timing, as revealed by auditory brainstem responses and electrophysiological recordings from VCN neurons. Although most features of signal transmission are normal, intermittent failures were observed in responses to trains of shocks, likely due to a failure in action potential conduction at branch points in Npr2 mutant afferent fibers. Our results show that Npr2 is necessary for the precise spatial organization typical of central auditory circuits, but that signals are still transmitted with normal timing, and that mutant mice can hear even with these deficits.
Author Summary
Millions of people suffer from debilitating hearing defects, ranging from a complete inability to detect sound to more subtle changes in how sounds are encoded by the nervous system. Many forms of deafness are due to mutations in genes that impair the development or function of hair cells, which are responsible for changing sound into electrical signals that can be processed by the brain. Both mice and humans carrying these mutations fail standard hearing tests. In contrast, very little is known about the genetic basis of central auditory processing disorders, which are poorly defined and difficult to diagnose, since these patients can still detect sounds. By finding genes that are required for the normal wiring of central auditory circuits in mice, we can investigate how changes at the circuit level affect circuit function and therefore improve our understanding of central auditory processing disorders. Here, we show that the natriuretic peptide receptor Npr2 is required to establish frequency maps in the mouse central auditory system. Surprisingly, despite a dramatic change in circuit organization, Npr2 mutant mice are still able to respond to sounds with normal sensitivity and timing, underscoring the need for better hearing diagnostic methods in mice as in humans.
PMCID: PMC4256264  PMID: 25473838
2.  Lack of an Association between CYP11B2 C-344T Gene Polymorphism and Ischemic Stroke: A Meta-Analysis of 7,710 Subjects 
PLoS ONE  2013;8(8):e68842.
The association between aldosterone synthase (CYP11B2) C-344T gene polymorphism and ischemic stroke remains controversial and ambiguous. To better explain the association between CYP11B2 polymorphism and ischemic stroke risk, a meta-analysis was performed.
Based on comprehensive searches of Medline, Embase, Web of Science, CNKI and CBM databases, we identified and abstracted outcome data from all articles to evaluate the association between CYP11B2 polymorphism and ischemic stroke. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed in all genetic models. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by Begg's funnel plot and Egger's regression test.
A total of 12 studies including 3,620 ischemic stroke cases and 4,090 controls were identified. There was no statistical evidence of association between CYP11B2 C-344T polymorphism and ischemic stroke in all genetic models (allelic model: OR = 1.19, 95% CI = 0.95–1.49; additive model: OR = 1.43, 95% CI = 0.91–2.27; dominant model: OR = 1.30, 95% CI = 0.89–1.89; and recessive model: OR = 1.24, 95% CI = 0.96–1.60). On subgroup analysis by ethnicity, similarly results were found in both Asians and non-Asians. For Asians, the combined ORs and 95% CIs were (allelic model: OR = 1.07, 95% CI = 0.87–1.32; additive model: OR = 1.15, 95% CI = 0.77–1.71; dominant model: OR = 1.13, 95% CI = 0.92–1.38; and recessive model: OR = 1.09, 95% CI = 0.84–1.40). For none-Asians, the combined ORs and 95% CIs were (allelic model: OR = 1.58, 95% CI = 0.90–2.76; additive model: OR = 2.37, 95% CI = 0.79–7.05; dominant model: OR = 1.79, 95% CI = 0.77–4.19; and recessive model: OR = 1.80, 95% CI = 0.96–3.36).
The present meta-analysis suggested that CYP11B2 C-344T polymorphism was unlikely contribute to ischemic stroke susceptibility.
PMCID: PMC3738569  PMID: 23950878
3.  The C825T Polymorphism of the G-Protein β3 Subunit Gene and Its Association with Hypertension and Stroke: An Updated Meta-Analysis 
PLoS ONE  2013;8(6):e65863.
Several epidemiological studies have evaluated the association between the GNB3 C825T polymorphism and hypertension or stroke. The results of these studies were inconsistent; therefore, we performed a meta-analysis to clarify these discrepancies.
We systematically searched the PubMed, Embase, Web of Science, CNKI, and CBM databases, and manually searched reference lists of relevant papers, meeting abstracts, and relevant journals. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for dominant, recessive, and allelic models. A fixed or random effects model was separately adopted depending on study heterogeneity. Subgroup and sensitivity analyses were performed to detect study heterogeneity and examine result stability, respectively. Publication bias was tested using funnel plots, the Egger's regression test, and Begg's test.
We screened 66 studies regarding hypertension and eight concerning stroke. A combined analysis showed that only the allelic model found a marginal association with hypertension (OR = 1.07, 95% CI = 1.01–1.13) and female gender (OR = 1.11, 95% CI = 0.99–1.24). However, no comparison models found an association with stroke (allelic model: OR = 1.11, 95% CI = 0.94–1.32; dominant model: OR = 1.16, 95% CI = 0.92–1.48; and recessive model: OR = 1.05, 95% CI = 0.97–1.14). Sensitivity analysis suggested that all models did not yield a relationship to hypertension or stroke among Asians. Besides, there was a lack of statistical association with hypertension in Caucasians, which maybe due to a small sample size. When we restricted the included studies to normal populations according to the Hardy–Weinberg equilibrium, no association was found.
There was no evidence indicating that the 825T allele or TT genotype was associated with hypertension or stroke in Asians or hypertension in Caucasians. However, further studies regarding Africans and other ethnicities are needed to identify further correlations.
PMCID: PMC3682991  PMID: 23799054
4.  The Multiple Functions of T Stellate/Multipolar/Chopper Cells in the Ventral Cochlear Nucleus 
Hearing research  2010;276(1-2):61-69.
Acoustic information is brought to the brain by auditory nerve fibers, all of which terminate in the cochlear nuclei, and is passed up the auditory pathway through the principal cells of the cochlear nuclei. A population of neurons variously known as T stellate, type I multipolar, planar multipolar, or chopper cells forms one of the major ascending auditory pathways through the brain stem. T Stellate cells are sharply tuned; as a population they encode the spectrum of sounds. In these neurons, phasic excitation from the auditory nerve is made more tonic by feed forward excitation, coactivation of inhibitory with excitatory inputs, relatively large excitatory currents through NMDA receptors, and relatively little synaptic depression. The mechanisms that make firing tonic also obscure the fine structure of sounds that is represented in the excitatory inputs from the auditory nerve and account for the characteristic chopping response patterns with which T stellate cells respond to tones. In contrast with other principal cells of the ventral cochlear nucleus (VCN), T stellate cells lack a low-voltage-activated potassium conductance and are therefore sensitive to small, steady, neuromodulating currents. The presence of cholinergic, serotonergic and noradrenergic receptors allows the excitability of these cells to be modulated by medial olivocochlear efferent neurons and by neuronal circuits associated with arousal. T Stellate cells deliver acoustic information to the ipsilateral dorsal cochlear nucleus (DCN), ventral nucleus of the trapezoid body (VNTB), periolivary regions around the lateral superior olivary nucleus (LSO), and to the contralateral ventral lemniscal nuclei (VNLL) and inferior colliculus (IC). It is likely that T stellate cells participate in feedback loops through both medial and lateral olivocochlear efferent neurons and they may be a source of ipsilateral excitation of the LSO.
PMCID: PMC3078527  PMID: 21056098
ventral cochlear nucleus; brainstem auditory pathways; ion channels; patch-clamp recording
5.  Connections and synaptic function in the posteroventral cochlear nucleus of deaf jerker mice 
Mutations in the gene that encodes espins can cause deafness and vestibular disorders; mice that are homozygous for the autosomal recessive, jerker mutation in the espin gene never hear. Extracellular injections of biocytin into the anteroventral cochlear nucleus (AVCN) revealed that although the cochlear nuclei are smaller in je/je mice, the topography in its innervation resembles that in wild type mice. Auditory nerve fibers innervate narrow, topographically organized, “isofrequency” bands in deaf animals over the ages examined, P18–P70. The projection of tuberculoventral cells was topographic in je/je as in wild type mice. Terminals of auditory nerve fibers in the multipolar cell area included both large and small endings whereas in the octopus cell area they were exclusively small boutons in je/je as in wild type mice but end bulbs near the nerve root of je/je animals were smaller than in hearing animals. In whole-cell recordings from targets of auditory nerve fibers, octopus and T stellate cells, miniature excitatory postsynaptic currents (mEPSCs) had similar shapes as in +/+, indicating that the properties of AMPA receptors were not affected by the mutation. In je/je animals the frequency of spontaneous mEPSCs was elevated and synaptic depression in responses to trains of shocks delivered at between 100 and 333 Hz was greater than in wild type mice indicating that the probability of neurotransmitter release was increased. The frequency of spontaneous mEPSCs and extent of synaptic depression were greater in octopus than in T stellate cells, in both wild type and je/je mice.
PMCID: PMC2553045  PMID: 18634002
brain stem; auditory pathway; auditory nerve; hearing impairment; espin
6.  In the ventral cochlear nucleus Kv1.1 and HCN1 are colocalized at surfaces of neurons that have low-voltage-activated and hyperpolarization-activated conductances 
Neuroscience  2008;154(1):77-86.
Principal cells of the ventral cochlear nucleus (VCN) differ in the magnitudes of low-voltage-activated potassium (gKL) and hyperpolarization-activated (gh) conductances that determine the time course of signaling. Octopus cells have large gKL (500 nS) and gh (150 nS), bushy cells have smaller gKL (80 nS) and gh (30 nS), and T stellate cells have little gKL and a small gh (20 nS). gKL arises through potassium channels of which ~ 60% contain Kv1.1 subunits; gh arises through channels that include HCN1 subunits. The surfaces of cell bodies and dendrites of octopus cells in the dorsocaudal pole, and of similar cells along the ventrolateral edge of the PVCN, were brightly labeled by an antibody against HCN1 that was colocalized with labeling for Kv1.1. More anteriorly neurons with little surface labeling were intermingled among cell bodies and dendrites with surface labeling for both proteins, likely corresponding to T stellate and bushy cells. The membrane-associated labeling patterns for Kv1.1 and HCN1 were consistent with what is known about the distribution and the electrophysiological properties of the principal cells of the VCN. The cytoplasm of large cells and axonal paranodes contained immunoflurorescent labeling for only Kv1.1.
PMCID: PMC2493296  PMID: 18424000
low-voltage-activated potassium conductance; hyperpolarization-activated conductance; hearing; auditory system; brainstem auditory nuclei

Results 1-6 (6)