Disrupted Cortical State Regulation in a Rat Model of Fragile X Syndrome.

Children with Fragile X syndrome (FXS) have deficits of attention and arousal. To begin to identify the neural causes of these deficits, we examined juvenile rats lacking the Fragile X mental retardation protein (FMR-KO) for disruption of cortical activity related to attention and arousal. Specifically, we examined the switching of visual cortex between activated and inactivated states that normally occurs during movement and quiet rest, respectively. In both wild-type and FMR-KO rats, during the third and fourth postnatal weeks cortical activity during periods of movement was dominated by an activated state with prominent 18-52 Hz activity. However, during quiet rest, when activity in wild-type rats became dominated by the inactivated state (3-9 Hz activity), FMR-KO rat cortex abnormally remained activated, resulting in increased high-frequency and reduced low-frequency power during rest. Firing rate correlations revealed reduced synchronization in FMR-KO rats, particularly between fast-spiking interneurons, that developmentally precede cortical state defects. Together our data suggest that disrupted inhibitory connectivity impairs the ability of visual cortex to regulate exit from the activated state in a behaviorally appropriate manner, potentially contributing to disrupted attention and sensory processing observed in children with FXS by making it more difficult to decrease cortical drive by unattended stimuli.

Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome.

Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the expected loss of visually evoked bursting at the same age as wild-type, two days before eye-opening. At later ages, during the third and fourth post-natal weeks, signs of mild hyper-excitability emerged. These included an increase in the visually-evoked firing of regular spiking, presumptive excitatory, neurons, and a reduced firing of fast-spiking, presumptive inhibitory, neurons. Our results show that early network changes in the FMR-KO rat arise at ages equivalent to fetal humans and have consequences for excitability that are opposite those found in adults. This suggests identification and treatment should begin early, and be tailored in an age-appropriate manner.

Modulation of hippocampal rhythms by subthreshold electric fields and network topology.

Theta (4-12 Hz) and gamma (30-80 Hz) rhythms are considered important for cortical and hippocampal function. Although several neuron types are implicated in rhythmogenesis, the exact cellular mechanisms remain unknown. Subthreshold electric fields provide a flexible, area-specific tool to modulate neural activity and directly test functional hypotheses. Here we present experimental and computational evidence of the interplay among hippocampal synaptic circuitry, neuronal morphology, external electric fields, and network activity. Electrophysiological data are used to constrain and validate an anatomically and biophysically realistic model of area CA1 containing pyramidal cells and two interneuron types: dendritic- and perisomatic-targeting. We report two lines of results: addressing the network structure capable of generating theta-modulated gamma rhythms, and demonstrating electric field effects on those rhythms. First, theta-modulated gamma rhythms require specific inhibitory connectivity. In one configuration, GABAergic axo-dendritic feedback on pyramidal cells is only effective in proximal but not distal layers. An alternative configuration requires two distinct perisomatic interneuron classes, one exclusively receiving excitatory contacts, the other additionally targeted by inhibition. These observations suggest novel roles for particular classes of oriens and basket cells. The second major finding is that subthreshold electric fields robustly alter the balance between different rhythms. Independent of network configuration, positive electric fields decrease, while negative fields increase the theta/gamma ratio. Moreover, electric fields differentially affect average theta frequency depending on specific synaptic connectivity. These results support the testable prediction that subthreshold electric fields can alter hippocampal rhythms, suggesting new approaches to explore their cognitive functions and underlying circuitry.

Switching between gamma and theta: Dynamic network control using subthreshold electric fields.

We implemented an experimentally observed orthogonal arrangement of theta and gamma generation circuitry in septotemporal and lamellar dimensions is a two-dimensional model of hippocampus. The model includes three types of cells: pyramidal, basket, and oriens lacunosum-moleculare (OLM) neurons. In this reduced model, application of continuous electric fields allowed us to switch between theta, gamma and mixed theta-gamma regimes without additional pharmacological manipulation. Electric field effects on individual neurons were modeled based on experimental data. Network simulation results predict a flexible experimental technique, which would employ adaptive subthreshold electric fields to continuously modulate neuronal ensemble activity, and can be used for testing cognitive correlates of oscillatory rhythms as well as for suppressing epileptiform activity.

Remote effects of highlights on gloss perception.

The perception of a glossy surface in a static monochromatic image can occur when a bright highlight is embedded in a compatible context of shading and a bounding contour. Some images naturally give rise to the impression that a surface has a uniform reflectance, characteristic of a shiny object, even though the highlight may only cover a small portion of the surface. Nonetheless, an observer's impression of gloss may be partial and nonuniform at image regions outside of a highlight. A rating scale and small probe points indicating image locations were used to investigate the differential perception of gloss within a single object. Gloss ratings given by observers were not uniform across a surface, but decreased as a function of distance from a highlight. When, by design, the distance from a highlight was uncoupled from the luminance value at corresponding probe points, the decrease in rated gloss correlated more with distance than with luminance change. Experiments also indicated that gloss ratings may change as a function of estimated surface distance, rather than as a function of image distance. Surface continuity affected gloss ratings, suggesting that surface and gloss processing are closely related.