Persistent enhancement of basolateral amygdala-dorsomedial striatum synapses causes compulsive-like behaviors in mice.

Compulsive behaviors are observed in a range of psychiatric disorders, however the neural substrates underlying the behaviors are not clearly defined. Here we show that the basolateral amygdala-dorsomedial striatum (BLA-DMS) circuit activation leads to the manifestation of compulsive-like behaviors. We revealed that the BLA neurons projecting to the DMS, mainly onto dopamine D1 receptor-expressing neurons, largely overlap with the neuronal population that responds to aversive predator stress, a widely used anxiogenic stressor. Specific optogenetic activation of the BLA-DMS circuit induced a strong anxiety response followed by compulsive grooming. Furthermore, we developed a mouse model for compulsivity displaying a wide spectrum of compulsive-like behaviors by chronically activating the BLA-DMS circuit. In these mice, persistent molecular changes at the BLA-DMS synapses observed were causally related to the compulsive-like phenotypes. Together, our study demonstrates the involvement of the BLA-DMS circuit in the emergence of enduring compulsive-like behaviors via its persistent synaptic changes.

Dynamic Changes in the Bridging Collaterals of the Basal Ganglia Circuitry Control Stress-Related Behaviors in Mice.

The basal ganglia network has been implicated in the control of adaptive behavior, possibly by integrating motor learning and motivational processes. Both positive and negative reinforcement appear to shape our behavioral adaptation by modulating the function of the basal ganglia. Here, we examined a transgenic mouse line (G2CT) in which synaptic transmissions onto the medium spiny neurons (MSNs) of the basal ganglia are depressed. We found that the level of collaterals from direct pathway MSNs in the external segment of the globus pallidus (GPe) ('bridging collaterals') was decreased in these mice, and this was accompanied by behavioral inhibition under stress. Furthermore, additional manipulations that could further decrease or restore the level of the bridging collaterals resulted in an increase in behavioral inhibition or active behavior in the G2CT mice, respectively. Collectively, our data indicate that the striatum of the basal ganglia network integrates negative emotions and controls appropriate coping responses in which the bridging collateral connections in the GPe play a critical regulatory role.

A novel color vision test for detection of diabetic macular edema.

PURPOSE: To determine the sensitivity of the Seoul National University (SNU) computerized color vision test for detecting diabetic macular edema. METHODS: From May to September 2003, a total of 73 eyes of 73 patients with diabetes mellitus were examined using the SNU computerized color vision test and optical coherence tomography (OCT). Color deficiency was quantified as the total error score on the SNU test and as error scores for each of four color quadrants corresponding to yellows (Q1), greens (Q2), blues (Q3), and reds (Q4). SNU error scores were assessed as a function of OCT foveal thickness and total macular volume (TMV). RESULTS: The error scores in Q1, Q2, Q3, and Q4 measured by the SNU color vision test increased with foveal thickness (P < 0.05), whereas they were not correlated with TMV. Total error scores, the summation of Q1 and Q3, the summation of Q2 and Q4, and blue-yellow (B-Y) error scores were significantly correlated with foveal thickness (P < 0.05), but not with TMV. CONCLUSIONS: The observed correlation between SNU color test error scores and foveal thickness indicates that the SNU test may be useful for detection and monitoring of diabetic macular edema.

A novel computerized visual acuity test for children.

PURPOSE: To investigate the efficacy of a computerized visual acuity test, the SNU visual acuity test for children. METHODS: Fifty-six children, ranging from 1 to 5 years of age, were included. In a dark room, children gazed at and followed a circular dot with 50% contrast moving at a fixed velocity of 10 pixels/sec on a computer monitor. Eye movement was captured using a charge coupled device camera and was expressed as coordinates on a graph. Movements of the eye and dot were superimposed on a graph and analyzed. Minimum visualized dot diameters were compared to the Teller visual acuity. RESULTS: Ten eyes (8.9%) of six children failed to perform the Teller visual acuity test, and two eyes (1.8%) of one patient failed to perform the SNU visual acuity test. The observed Teller visual acuity and SNU visual acuity were significantly correlated (p < 0.001). Visual angle degrees converted from the Teller visual acuity and SNU visual acuity were also significantly correlated (p < 0.001). CONCLUSION: The SNU visual acuity using moving targets correlated well with Teller visual acuity and was more applicable than the Teller acuity test. Therefore, the SNU visual acuity test has potential clinical applications for children.

Efficacy of a computerized optokinetic nystagmus test in prediction of visual acuity of better than 20/200.

PURPOSE: To evaluate the efficacy of a computerized optokinetic nystagmus (OKN) test in detecting visual acuity (VA) of >20/200. METHODS: This was a combined retrospective and prospective, noninterventional study. In phase I of the study, data from 168 eyes of 154 subjects who underwent the computerized objective VA test using OKN responses at Seoul National University Bundang Hospital were reviewed and reanalyzed, and a table for predicting the range of subjective VA for each step of objective VA was made. From the table, the cutoff value for detecting VA of >20/200 was determined. In phase II of the study, the distribution of subjective VA according to each objective VA step was determined for 80 eyes of 40 subjects at Seoul Veteran's Hospital. The sensitivity and the specificity of our cutoff value were evaluated in the two groups. RESULTS: No significant difference was found in the distribution of subjective VA according to objective VA steps between the two groups. For the subjects in phase I of the study, the sensitivity of our cutoff value was 91.7% and the specificity was 88.3%. For patients in phase II of the study, the sensitivity of our cutoff was 86% and the specificity was 96.7%. CONCLUSIONS: This study shows that an objective VA test using OKN responses can be effective in predicting real VA and detecting VA of >20/200.

Objective measurement of distance visual acuity determined by computerized optokinetic nystagmus test.

PURPOSE: To investigate the efficacy of a computerized optokinetic nystagmus (OKN) test in evaluating the objective distance visual acuity and to determine the correlation between subjective and objective visual acuities. METHODS: This prospective, noninterventional study included 83 eyes of 83 volunteers. Objective visual acuity was defined as the smallest size stripe that evoked the OKN response (induction method) or as the smallest dot size that suppressed the OKN response (suppression method). Distance visual acuity was measured by computerized OKN and infrared oculography at distance. The reproducibility of the test was evaluated by intraclass correlation coefficient (ICC). The correlation between measured objective and subjective visual acuity was then evaluated with linear regression analysis. Subjects were grouped according to their objective visual acuity, and the mean subjective visual acuities were compared with those of the objective visual acuity groups. RESULTS: There was a significant correlation between distance objective and subjective visual acuity (correlation coefficient R(2), induction method:suppression method = 0.566:0.832, P < 0.05). The mean subjective visual acuity was significantly different in the objective visual acuity groups (Welch's ANOVA, P = 0.000 for induction and suppression methods). The objective visual acuity test showed good reproducibility (ICC; induction method:suppression method = 0.945:0.988, P < 0.05). CONCLUSIONS: The computerized OKN test could serve as an objective and reliable tool for assessing distance visual acuity.

The effect of rod domain A148V mutation of neurofilament light chain on filament formation.

Neurofilaments (NFs) are neuronal intermediate filaments composed of light (NF-L), middle (NF-M), and heavy (NF-H) subunits. NF-L self-assembles into a "core" filament with which NF-M or NF-H co-assembles to form the neuronal intermediate filament. Recent reports show that point mutations of the NF-L gene result in Charcot-Marie-Tooth disease (CMT). However, the most recently described rod domain mutant of human NF-L (A148V) has not been characterized in cellular level. We cloned human NF-L and used it to engineer the A148V. In phenotypic analysis using SW13 cells, A148V mutation completely abolished filament formation despite of presence of NF-M. Moreover, A148V mutation reduced the levels of in vitro self-assembly using GST-NF-L (H/R) fusion protein whereas control (A296T) mutant did not affect the filament formation. These results suggest that alanine at position 148 is essentially required for NF-L self-assembly leading to subsequent filament formation in neuronal cells.

In vitro assay of neurofilament light chain self-assembly using truncated mutants.

Neurofilaments (NFs) are heteropolymers composed of light (NF-L), middle (NF-M), and heavy (NF-H) subunits, present in most neurons. NF-L polymerizes on its own to provide a scaffold on which regular NFs form via the cross-bridging of NF-M or NF-H. To clarify the mechanism of regulation of NF-L self-assembly, we developed an assay using truncated mutant NF-L fused to glutathione-S transferase (GST). Western immunoblotting data show that the GST-fused head-rod domains of NF-L are necessary and sufficient for detecting assembled NF-L. The levels of self-assembled NF-L subunits detected using GST fusion proteins were consistent with those detected by electron microscopy and turbidity assay. Our results collectively imply that GST-fused head-rod domains of NF-L are critical tools for analyzing NF-L self-assembly in vitro.

Objective measurement of visual acuity by optokinetic response determination in patients with ocular diseases.

PURPOSE: To investigate the efficacy of optokinetic nystagmus (OKN) suppression and induction methods for the objective estimation of visual acuities in patients with various ocular diseases. DESIGN: Prospective, descriptive study. METHODS: One hundred seventy-three eyes of 89 patients aged between 27 and 75 years who registered at our institution from January to December 2004 were prospectively enrolled onto this study. Ocular diseases included generalized retinal diseases (47 eyes), media opacity (32 eyes), refractive errors (31 eyes), glaucoma (27 eyes), maculopathies (26 eyes), and optic neuropathies (10 eyes). Horizontal optokinetic stimuli were presented on a 17-inch monitor screen at a distance of 40 cm from the subject in a dark room. Horizontal eye movements were recorded in each eye separately by infrared oculography. Objective visual acuities measured by using OKN suppression or induction methods were compared with subjective visual acuity assessments. The logarithm of minimal angle of resolution visual acuity was 1.03, and ranged from -0.08 to hand movement. RESULTS: Linear regression identified minimum stripe stimuli required to induce OKN by using the OKN induction method, and the minimum dot size required to suppress OKN was found to be correlated with subjective visual acuity (P<.01). The induction method was useful in patients with visual acuities of 20/60 or worse, and the suppression method was useful in patients with visual acuities of 20/200 or better. CONCLUSIONS: Combined use of the OKN induction and suppression methods provides a satisfactory means of determining objective visual acuity.