Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction.

Purposeful induction of fever for healing, including the treatment of epilepsy, was used over 2000 years ago by Hippocrates. More recently, fever has been demonstrated to rescue behavioral abnormalities in children with autism. However, the mechanism of fever benefit has remained elusive due in large part to the lack of appropriate human disease models recapitulating the fever effect. Pathological mutations in the IQSEC2 gene are frequently seen in children presenting with intellectual disability, autism and epilepsy. We recently described a murine A350V IQSEC2 disease model, which recapitulates important aspects of the human A350V IQSEC2 disease phenotype and the favorable response to a prolonged and sustained rise in body core temperature in a child with the mutation. Our goal has been to use this system to understand the mechanism of fever benefit and then develop drugs that can mimic this effect and reduce IQSEC2-associated morbidity. In this study, we first demonstrate a reduction in seizures in the mouse model following brief periods of heat therapy, similar to what was observed in a child with the mutation. We then show that brief heat therapy is associated with the correction of synaptic dysfunction in neuronal cultures of A350V mice, likely mediated by Arf6-GTP.

Stimulus-specific adaptation: can it be a neural correlate of behavioral habituation?

Habituation is the most basic form of learning, yet many gaps remain in our understanding of its underlying neural mechanisms. We demonstrate that in the owl's optic tectum (OT), a single, low-level, relatively short auditory stimulus is sufficient to induce a significant reduction in the neural response to a stimulus presented up to 60 s later. This type of neural adaptation was absent in neurons from the central nucleus of the inferior colliculus and from the auditory thalamus; however, it was apparent in the OT and the forebrain entopallium. By presenting sequences that alternate between two different auditory stimuli, we show that this long-lasting adaptation is stimulus specific. The response to an odd stimulus in the sequence was not smaller than the response to the same stimulus when it was first in the sequence. Finally, we measured the habituation of reflexive eye movements and show that the behavioral habituation is correlated with the neural adaptation. The finding of a long-lasting specific adaptation in areas related to the gaze control system and not elsewhere suggests its involvement in habituation processes and opens new directions for research on mechanisms of habituation.

Interactions between stimulus-specific adaptation and visual auditory integration in the forebrain of the barn owl.

Neural adaptation and visual auditory integration are two well studied and common phenomena in the brain, yet little is known about the interaction between them. In the present study, we investigated a visual forebrain area in barn owls, the entopallium (E), which has been shown recently to encompass auditory responses as well. Responses of neurons to sequences of visual, auditory, and bimodal (visual and auditory together) events were analyzed. Sequences comprised two stimuli, one with a low probability of occurrence and the other with a high probability. Neurons in the E tended to respond more strongly to low probability visual stimuli than to high probability stimuli. Such a phenomenon is known as stimulus-specific adaptation (SSA) and is considered to be a neural correlate of change detection. Responses to the corresponding auditory sequences did not reveal an equivalent tendency. Interestingly, however, SSA to bimodal events was stronger than to visual events alone. This enhancement was apparent when the visual and auditory stimuli were presented from matching locations in space (congruent) but not when the bimodal stimuli were spatially incongruent. These findings suggest that the ongoing task of detecting unexpected events can benefit from the integration of visual and auditory information.

Multiple manifestations of microstimulation in the optic tectum: eye movements, pupil dilations, and sensory priming.

It is well established that the optic tectum (or its mammalian homologue, the superior colliculus) is involved in directing gaze toward salient stimuli. However, salient stimuli typically induce orienting responses beyond gaze shifts. The role of the optic tectum in generating responses such as pupil dilation, galvanic responses, or covert shifts is not clear. In the present work, we studied the effects of microstimulation in the optic tectum of the barn owl (Tyto alba) on pupil diameter and on eye shifts. Experiments were conducted in lightly anesthetized head-restrained barn owls. We report that low-level microstimulation in the deep layers of the optic tectum readily induced pupil dilation responses (PDRs), as well as small eye movements. Electrically evoked PDRs, similar to acoustically evoked PDRs, were long-lasting and habituated to repeated stimuli. We further show that microstimulation in the external nucleus of the inferior colliculus also induced PDRs. Finally, in experiments in which tectal microstimulations were coupled with acoustic stimuli, we show a tendency of the microstimulation to enhance pupil responses and eye shifts to previously habituated acoustic stimuli. The enhancement was dependent on the site of stimulation in the tectal spatial map; responses to sounds with spatial cues that matched the site of stimulation were more enhanced compared with sounds with spatial cues that did not match. These results suggest that the optic tectum is directly involved in autonomic orienting reflexes as well as in gaze shifts, highlighting the central role of the optic tectum in mediating the body responses to salient stimuli.