Tomoyo Isoguchi Shiramatsu

Cortical Mapping of Mismatch Negativity with Deviance Detection Property in Rat

Mismatch Negativity (MMN) is an N-methyl-d-aspartic acid (NMDA)-mediated, negative deflection in human auditory evoked potentials in response to a cognitively discriminable change. MMN-like responses have been extensively investigated in animal models, but the existence of MMN equivalent is still controversial. In this study, we aimed to investigate how closely the putative MMN (MMNp) in rats exhibited the comparable properties of human MMN. We used a surface microelectrode array with a grid of 10×7 recording sites within an area of 4.5×3.0 mm to densely map evoked potentials in the auditory cortex of anesthetized rats under the oddball paradigm. Firstly, like human MMN, deviant stimuli elicited negative deflections in auditory evoked potentials following the positive middle-latency response, termed P1. Secondly, MMNp exhibited deviance-detecting property, which could not be explained by simple stimulus specific adaptation (SSA). Thirdly, this MMNp occurred focally in the auditory cortex, including both the core and belt regions, while P1 activation focus was obtained in the core region, indicating that both P1 and MMNp are generated in the auditory cortex, yet the sources of these signals do not completely overlap. Fourthly, MMNp significantly decreased after the application of AP5 (D-(-)-2-amino-5-phosphonopentanoic acid), an antagonist at NMDA receptors. In stark contrast, AP5 affected neither P1 amplitude nor SSA of P1. These results provide compelling evidence that the MMNp we have examined in rats is functionally comparable to human MMN. The present work will stimulate translational research into MMN, which may help bridge the gap between electroencephalography (EEG)/magnetoencephalography (MEG) studies in humans and electrophysiological studies in animals.

Modulation of cortical synchrony by vagus nerve stimulation in adult rats

Vagus nerve stimulation (VNS) is a palliative treatment for intractable epilepsy. Therapeutic mechanisms of VNS have not been elucidated. In this study, we measured the local field potential (LFP) with high-spatial resolution using a microelectrode array in adult rats, and analyzed VNS-evoked phase modulation at a local network level. Eight adult Wistar rats (270 - 330 g) were used. Each rat underwent implantation of VNS system (Cyberonics, Houston, TX., USA) under 1.5% isoflurane anesthesia. One week after implantation, right temporal craniotomy was performed under the same as previous anesthesia. Subsequently, a microelectrode array was placed in the temporal lobe cortex, and LFP was recorded with sampling rate of 1000 Hz. Phase-locking value (PLV) between all pairs of electrodes in varied frequency bands was calculated in order to evaluate the effect of VNS in terms of synchrony of neuronal activities. PLV was calculated both in a normal state and in an epileptic state induced by kainic acid. VNS increased PLV in a normal state, particularly in high-γ band. In an epileptic state, VNS increased PLV in high-γ band, and decreased in d and low-β bands. VNS modulates synchrony in a band-specific and state-dependent manner. VNS might keep cortical synchrony within the optimal state.

Simultaneous microelectrode recording of layered structure of cortex and tonotopic structure of thalamus in the auditory pathway

Simultaneous characterization of layer-specific activation in the cortex and topographically organized activation in the thalamus brings substantial benefits to advance the understanding of the sensory/motor functions. We designed a silicon-probe microelectrode array to simultaneously characterize the primary auditory cortex (A1) and thalamus (medial geniculate body; MGB), which are aligned in the dosro-lateral to ventro-medial axis perpendicular to the cortical surface of A1. The array had 3 shanks with 6-mm length. On each shank, 15 recording sites were made at the tip for MGB and 17 sites were made at the bottom for A1. A laser displacement meter was proved useful to make appropriate insertion of the array probe at a right angle with respect to the cortical surface. Our experiments in vivo demonstrated the capability of the designed array to investigate the thalamo-cortical interaction between tonotopically organized activities in the thalamus and layer-specific activities in the cortex.

Combined neural measurement with surface and depth microelectrode array for topographic and layer-specific characterization in the auditory cortex and thalamus

Interaction between bottom-up and top-down information processing between the auditory cortex (AC) and thalamus (medial geniculate body; MGB) has been considered important for auditory perception. In this study, we developed an experimental system consisting of a surface microelectrode array and depth microelectrode array to comprehensively investigate the thalamo-cortical system. The combined use of two types of electrode array was able to simultaneously characterize the superficial as well as layer-specific activities in AC. We measured tone-evoked local field potentials and multi-unit activities from anesthetized rats. First, we demonstrated that tonotopic maps from the surface and depth electrode array agreed with previous studies. Second, electrical stimulation to MGB induced deflection in local field potentials, both in AC and MGB. These results indicate the feasibility and efficacy of our experimental system to characterize the thalamo-cortical interaction in the auditory pathway.

Covariation of pupillary and auditory cortical activity in rats under isoflurane anesthesia

Very slow fluctuations of spontaneous activities significantly influence not only behavioral performance in a conscious state, but also neural activities in an unconscious state. Covariation of pupil and cortical activities may lend important insights into the state-dependent modulation of stimulus encoding, yet this phenomenon has received little attention, especially with regard to non-visual cortices. In the present study, we investigated co-fluctuation of pupil size and neural activity in the auditory cortex of rats under isoflurane anesthesia. Pupil fluctuation consisted of longitudinal irregular shifts, and 1-min cyclic modulations. Both spontaneous and auditory-evoked potentials (AEPs) covaried with the longitudinal fluctuation of pupil size, but not with the 1-min cycle. Pupil size exhibited a positive correlation with spontaneous activity and negative correlation with AEP amplitude, particularly when the pupil size was beyond the normal range. Stimulus-specific adaptation characterized using an oddball paradigm was less dependent on pupil size than AEP. In contrast to the cortical activity, heart rate covaried with pupil size with the 1-min oscillatory component, but not the non-oscillatory component. Furthermore, light exposure induced the pupil reflex through the autonomic system, but did not modify cortical activity, indicating that autonomic activity was not causing the cortical modulation. These results together suggest that cortical activities spontaneously covary with pupillary activity through central cholinergic modulation that triggers sympathetic nerve activation. Such a state-dependent property may be a confounding factor in cortical electrophysiology studies.

Decoding of the sound frequency from the steady-state neural activities in rat auditory cortex

In the auditory cortex, onset activities have been extensively investigated as a cortical representation of sound information such as sound frequency. Yet, less attention has been paid to date to steady-state activities following the onset activities. In this study, we used machine learning to investigate whether steady-state activities in the presence of continuous sounds represent the sound frequency. Sparse Logistic Regression (SLR) decoded the sound frequency from band specific power or phase locking value (PLV) of local field potentials (LFP) from the fourth layer of the auditory cortex of anesthetized rats. Consequently, we found that SLR was able to decode the sound frequency from steady-state neural activities as well as onset activities. This result demonstrates that the steady-state activities contain information about the sound such as sound frequency.

Preference test of sound among multiple alternatives in rats

Conditioned place preference (CPP) tests in rodents have been well established to measure preference induced by secondary reinforcing properties, but conventional assays are not sensitive enough to measure innate, weak preference, or the primary reinforcing property of a conditioned stimulus. We designed a novel CPP assay with better sensitivity and efficiency in quantifying and ranking preference of particular sounds among multiple alternatives. Each test tone was presented according to the location of free-moving rats in the arena, where assignment of location to each tone changed in every 20-s session. We demonstrated that our assay was able to rank tone preference among 4 alternatives within 12.5 min (125 s (habituation) + 25 s/sessions × 25 sessions). In order to measure and rank sound preference, we attempted to use sojourn times with each test sound (T¯), and a preference index (PI) based on transition matrices of initial and end sounds in every session. Both T¯ and PI revealed similar trends of innate preference in which rats preferred test conditions in the following order: silence, 40-, 20-, then 10-kHz tones. Further, rats exhibited a change in preference after an classical conditioning of the 20-kHz tone with a rewarding microstimulation of the dopaminergic system. We also demonstrated that PI was a more robust and sensitive indicator than T¯ when the locomotion activity level of rats became low due to habituation to the assay repeated over sessions. Thus, our assay offers a novel method of evaluating auditory preference that is superior to conventional CPP assays, offering promising prospects in the field of sensory neuroscience.