Hearing loss and impaired short-term memory in an Alzheimer's disease mouse model of amyloid-beta pathology.

Current evidence supports the link between hearing loss and Alzheimer's disease (AD). However, few studies report the hearing status of AD mice compared to wild-type mice. This study aimed to compare hearing thresholds and short-term memory (STM) performance of an AD (APPNL-G-F) mouse model of amyloid-beta (Aꞵ) pathology with C57BL/6 J and CBA/CaJ mice across age. The auditory brainstem response (ABR) test, using click and five tone-burst (TB) stimuli, was recorded at 2, 4, 6, 9, and 12 months. The novel object recognition (NOR) test, a measure of STM, was conducted at 6 and 12 months. While hearing thresholds were almost preserved in CBA/CaJ mice, they were not recorded at high frequencies with age in C57BL/6 J and AD mice, leading to island hearing (severe to profound hearing loss) at 9 and 12 months. AD mice showed increased hearing thresholds in TB8 and TB16 kHz at 6 and 9 months compared to C57BL/6 J mice. NOR findings were evidence of impaired STM in both C57BL/6 J and AD mice relative to CBA/CaJ mice, and a relationship was found between hearing thresholds and NOR measures in three groups. The findings were in support of the link between the degree of hearing loss and impaired STM.

Spatiotemporal structure of sensory-evoked and spontaneous activity revealed by mesoscale imaging in anesthetized and awake mice.

Stimuli-evoked and spontaneous brain activity propagates across the cortex in diverse spatiotemporal patterns. Despite extensive studies, the relationship between spontaneous and evoked activity is poorly understood. We investigate this relationship by comparing the amplitude, speed, direction, and complexity of propagation trajectories of spontaneous and evoked activity elicited with visual, auditory, and tactile stimuli using mesoscale wide-field imaging in mice. For both spontaneous and evoked activity, the speed and direction of propagation is modulated by the amplitude. However, spontaneous activity has a higher complexity of the propagation trajectories. For low stimulus strengths, evoked activity amplitude and speed is similar to that of spontaneous activity but becomes dissimilar at higher stimulus strengths. These findings are consistent with observations that primary sensory areas receive widespread inputs from other cortical regions, and during rest, the cortex tends to reactivate traces of complex multisensory experiences that might have occurred in exhibition of different behaviors.

Prenatal stress dysregulates resting-state functional connectivity and sensory motifs.

Prenatal stress (PS) can impact fetal brain structure and function and contribute to higher vulnerability to neurodevelopmental and neuropsychiatric disorders. To understand how PS alters evoked and spontaneous neocortical activity and intrinsic brain functional connectivity, mesoscale voltage imaging was performed in adult C57BL/6NJ mice that had been exposed to auditory stress on gestational days 12-16, the age at which neocortex is developing. PS mice had a four-fold higher basal corticosterone level and reduced amplitude of cortical sensory-evoked responses to visual, auditory, whisker, forelimb, and hindlimb stimuli. Relative to control animals, PS led to a general reduction of resting-state functional connectivity, as well as reduced inter-modular connectivity, enhanced intra-modular connectivity, and altered frequency of auditory and forelimb spontaneous sensory motifs. These resting-state changes resulted in a cortical connectivity pattern featuring disjoint but tight modules and a decline in network efficiency. The findings demonstrate that cortical connectivity is sensitive to PS and exposed offspring may be at risk for adult stress-related neuropsychiatric disorders.

Corticosterone response to gestational stress and postpartum memory function in mice.

Maternal stress is a common adversity during pregnancy. Gestational corticosterone alternations are thought to contribute to the etiology of postpartum behavioral disturbances. However, the impact of stress during pregnancy, in particular noise exposure, on gestational corticosterone fluctuations and spatial cognition in postpartum mice has not been fully understood yet. We hypothesized that noise exposure during pregnancy negatively affects gestational corticosterone levels and postpartum memory function in the dams similar to the physical stressors. Pregnant C57BL/6 mice were randomly assigned to either one of two stress conditions or a control condition. The noise stress (NS) was induced by presenting a loud intermittent 3000 Hz frequency on gestational days (GDs) 12, 14, and 16 for 24 hours, whereas the physical stress (PS) consisted of restraint and exposure to an elevated platform on GDs 12-16. Plasma corticosterone level was collected on GDs 11 and 17, and Morris water task (MWT) was carried out 30 days after parturition. Compared to the control group, the level of corticosterone in the stressed groups was significantly increased on GD17 relative to GD11. Significantly longer swim time and lower swim speed were observed in both stressed groups relative to the control group. Probe time was significantly shorter in the NS group than the other groups. The delta corticosterone level was significantly correlated with the swim time as well as the probe time in the three groups. Given the results, the adverse effects of gestational noise exposure on the hypothalamic pituitary-adrenal (HPA) axis activation and postpartum spatial learning and memory function were as large as/ or a bit stronger than the physical stresses. The findings suggest the significance of conservation against loud noise exposure in daily living, as well as need to further notice to the different aspects of gestational stress in mothers' behavior like offspring.

Optical-flow analysis toolbox for characterization of spatiotemporal dynamics in mesoscale optical imaging of brain activity.

Wide-field optical imaging techniques constitute powerful tools to investigate mesoscale neuronal activity. The sampled data constitutes a sequence of image frames in which one can investigate the flow of brain activity starting and terminating at source and sink locations respectively. Approaches to the analyses of information flow include qualitative assessment to identify sources and sinks of activity as well as their trajectories, and quantitative measurements based on computing the temporal variation of the intensity of pixels. Furthermore, in a few studies estimates of wave motion have been reported using optical-flow techniques from computer vision. However, a comprehensive toolbox for the quantitative analyses of mesoscale brain activity data is still lacking. We present a graphical-user-interface toolbox based in Matlab® for investigating the spatiotemporal dynamics of mesoscale brain activity using optical-flow analyses. The toolbox includes the implementation of three optical-flow methods namely Horn-Schunck, Combined Local-Global, and Temporospatial algorithms for estimating velocity vector fields of flow of mesoscale brain activity. From the velocity vector fields we determined the locations of sources and sinks as well as the trajectories and temporal velocities of flow of activity. Using simulated data as well as experimentally derived sensory-evoked voltage and calcium imaging data from mice, we compared the efficacy of the three optical-flow methods for determining spatiotemporal dynamics. Our results indicate that the combined local-global method we employed, yields the best results for estimating wave motion. The automated approach permits rapid and effective quantification of mesoscale brain dynamics and may facilitate the study of brain function in response to new experiences or pathology.