The temporal impulse response function in infantile nystagmus.

Despite rapid to-and-fro motion of the retinal image that results from their incessant involuntary eye movements, persons with infantile nystagmus (IN) rarely report the perception of motion smear. We performed two experiments to determine if the reduction of perceived motion smear in persons with IN is associated with an increase in the speed of the temporal impulse response. In Experiment 1, increment thresholds were determined for pairs of successively presented flashes of a long horizontal line, presented on a 65-cd/m2 background field. The stimulus-onset asynchrony (SOA) between the first and second flash varied from 5.9 to 234 ms. In experiment 2, temporal contrast sensitivity functions were determined for a 3-cpd horizontal square-wave grating that underwent counterphase flicker at temporal frequencies between 1 and 40 Hz. Data were obtained for 2 subjects with predominantly pendular IN and 8 normal observers in Experiment 1 and for 3 subjects with IN and 4 normal observers in Experiment 2. Temporal impulse response functions (TIRFs) were estimated as the impulse response of a linear second-order system that provided the best fit to the increment threshold data in Experiment 1 and to the temporal contrast sensitivity functions in Experiment 2. Estimated TIRFs of the subjects with pendular IN have natural temporal frequencies that are significantly faster than those of normal observers (ca. 13 vs. 9 Hz), indicating an accelerated temporal response to visual stimuli. This increase in response speed is too small to account by itself for the virtual absence of perceived motion smear in subjects with IN, and additional neural mechanisms are considered.

CONFORMATIONAL CHANGES IN THE EXTRACELLULAR DOMAIN OF GLUTAMATE RECEPTORS

The family of membrane protein called glutamate receptors play an important role in the central nervous system in mediating signaling between neurons. Glutamate receptors are involved in the elaborate game that nerve cells play with each other in order to control movement, memory, and learning. Neurons achieve this communication by rapidly converting electrical signals into chemical signals and then converting them back into electrical signals. To propagate an electrical impulse, neurons in the brain launch bursts of neurotransmitter molecules like glutamate at the junction between neurons, called the synapse. Glutamate receptors are found lodged in the membranes of the post-synaptic neuron. They receive the burst of neurotransmitters and respond by fielding the neurotransmitters and opening ion channels. Glutamate receptors have been implicated in a number of neuropathologies like ischemia, stroke and amyotrophic lateral sclerosis. Specifically, the NMDA subtype of glutamate receptors has been linked to the onset of Alzheimer’s disease and the subsequent degeneration of neuronal cells. While crystal structures of AMPA and kainate subtypes of glutamate receptors have provided valuable information regarding the assembly and mechanism of activation; little is known about the NMDA receptors. Even the basic question of receptor assembly still remains unanswered. Therefore, to gain a clear understanding of how the receptors are assembled and how agonist binding gets translated to channel opening, I have used a technique called Luminescence Resonance Energy Transfer (LRET). LRET offers the unique advantage of tracking large scale conformational changes associated with receptor activation and desensitization. In this dissertation, LRET, in combination with biochemical and electrophysiological studies, were performed on the NMDA receptors to draw a correlation between structure and function. NMDA receptor subtypes GluN1 and GluN2A were modified such that fluorophores could be introduced at specific sites to determine their pattern of assembly. The results indicated that the GluN1 subunits assembled across each other in a diagonal manner to form a functional receptor. Once the subunit arrangement was established, this was used as a model to further examine the mechanism of activation in this subtype of glutamate receptor. Using LRET, the correlation between cleft closure and activation was tested for both the GluN1 and GluN2A subunit of the NMDA receptor in response to agonists of varying efficacies. These investigations revealed that cleft closure plays a major role in the mechanism of activation in the NMDA receptor, similar to the AMPA and kainate subtypes. Therefore, suggesting that the mechanism of activation is conserved across the different subtypes of glutamate receptors.

Aggression, impulsivity and serotonin in drug dependence

Aggression, impulsivity, and central serotonergic function were evaluated in two groups of human volunteers; one group having a history of substance dependence (DRUG+) and another group with no drug use history (DRUG$-$). The hypothesis was that DRUG+ subjects would be more aggressive, more impulsive, and have attenuated serotonergic function. Results showed that DRUG+ subjects behaved more aggressively in a computer paradigm of aggression and also reported more aggression on questionnaires than DRUG$-$ subjects. In a computer paradigm of impulsivity, the DRUG+ group showed a lesser ability to delay gratification than the DRUG$-$ group in the last session of testing. The DRUG+ subjects also reported more venturesomeness and problems associated with low impulse control on questionnaires. Serotonergic function was measured through the neuroendocrine and hypothermic response to an orally administered serotonin (5-HT) agonist specific to the 5-HT$\rm\sb{1A}$ receptor subtype (ipsapirone). The neuroendocrine responses did not differ between DRUG$\pm$ groups, indicating no difference in the sensitivity of the presynaptic or postsynaptic 5-HT$\rm\sb{1A}$ receptors. An unexpected result was that the indicator hormone, cortisol, was at a lower baseline level in the DRUG+ group than the DRUG$-$ group. Lowered cortisol levels have been previously noted in children at high risk foul antisociality and future drug use. A principal components analysis including impulsivity, aggression, and serotonergic function measures produced three unique factors. The factors, Antisocial Tendency and Self-Control and Serotonergic Function combined to produce a significant regression equation explaining 36% of variability in the DRUG$\pm$ groups. These factors included measures of aggression, impulsivity, mood, and educational attainment. These results suggest that the current measures of aggression and impulsivity were predictive of a drug dependence disorder but that neuroendocrine function is not yet a useful indicator of drug dependence status. ^