JPH0314127B2 - - Google Patents

Abstract

PURPOSE:To analyze the action state for a long time by discriminating and binarizing respective levels of action and non-action of a body motion signal and respective levels of deep sleep and nondeep sleep of a brain wave signal and specifying an REM sleep state from the external to generate 4-state time series data. CONSTITUTION:A maximum amplitude BM1 at every one second and an integral value D1 of 2-4Hz components at every one second are given to a recording meter 19 from a body motion detecting transducer 10 and a brain wave detecting electrode 11 which are provided on a small animal 9 for medicine and pharmacology, and they are inputted to the first analyzing block 25 also through an A/D converter 18 and an input data storage device 23 together with a reference value obtained from a monitor display device 22 and are binarized and are classified to an active state, a deep sleep state, and a still state. Further, the REM sleep state is read and interrupted from the recording meter 19 to generate 4- state time series data, and a relative body motion state is set by the second analyzing block 26, and the still state is classified into small groups in accordance with states before and after the still state by the third analyzing block 27 and is recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) Technical Field of the Invention The present invention relates to a small animal behavioral state analyzer used in the medical and pharmaceutical fields. In the early stages of new drug development, a prototype drug compound or a similar compound is administered to small animals, and a wide range of systemic symptoms and behaviors are observed, and the main effect of the compound's pharmacological activity and the approximate degree of acute toxicity are determined. It is evaluated. In addition, animal experiments called long-term safety tests are required for pharmaceuticals and foods. The device of the present invention is used as a labor-saving device for animal experiments in the above-mentioned screening and safety testing of new drugs.

(2) Technical background of the invention The field of studying the structure and function of the brain using microelectrodes is called neurophysiology, and has been the mainstream of physiology for the past several decades. Significant progress in this field has been made possible by the establishment of experimental techniques, namely techniques that bring electrodes into direct contact with central nerve cells in the brain. This technology consists of a sophisticated device that mechanically fixes the brain of a laboratory animal and inserts a microelectrode into the brain, and a technique that estimates the anatomical location of the central nerve cells to be measured from outside the skull. It is something.

Because the experiments require skilled craftsmanship, the experimental animals used are cats, which have large brains relative to their body weight, and an international common understanding of central nervous physiology has been formed centering on the cat brain. , which was gradually extended to monkeys and rats.

Throughout this history, mice were the smallest experimental animals, with small brains, and were ignored in central electrophysiology, and the development of ancillary experimental equipment was not carried out systematically. Nakatsuta.

However, as knowledge about brain structure and function has been accumulated through acute experiments, there has been a gradual shift towards analysis of brain functions through long-term measurements (chronic experiments), while the establishment of biochemical microtechniques and their associated Significant progress has been made in the knowledge of substance metabolism related to the structure and function of the modern brain. In addition, technology for artificially manipulating genetic information has been established, and life science is making dramatic progress, centering on experimental animals such as mice.

Against the background of such progress in life sciences, the need for technology to measure the mental and individual functions of the brain over long periods of time has rapidly increased. One of the promising technologies that can meet this demand is the establishment of electrophysiological and psychological measurement and analysis techniques that make it possible to analyze the condition of individuals over long periods of time using mice. In other words, we investigated the metabolism of physiologically active substances in the brain while genetically manipulating mice, and compared the results of analysis using electron microscopy, which confirmed the relationship with structure, with changes in the state of individual mice (individual functions). It can be said that we have reached a stage where new life science knowledge is expected for the first time.

Sleep analysis is essential for the analysis of the state of discovery of individual animal functions, and brain wave analysis is also essential for quantifying the sleep state. However, the analysis of brain waves necessary and sufficient for sleep analysis is based on pattern recognition (inspection) of brain wave images recorded on recording paper, and large-scale and long-term experiments and analyzes require a huge amount of manpower and time. It was impossible without consumption. In other words, it is no exaggeration to say that because online technology for measurement and analysis had not been established, it remained unrelated to advances in computers.

(3) Conventional technology and problems In the past, behavioral state analysis devices that use both behavior measurement and sleep measurement of small animals to automatically classify detailed states of small animals such as wakefulness and sleep states for each unit of time have not been developed. Doesn't exist.

Traditionally, it was called polygraphy,
A method was used in which the physiological functions of various animals were converted into electrical signals, recorded in parallel on recording paper, and researchers read these signals, compared them, quantified them, and diagnosed the phenomenon. .

Currently, when it comes to measuring single physiological functions in animals,
Various measuring devices are commercially available. Regarding the measurement of animal behavior, methods for detecting animal movement include methods that use a breeding cage that rotates with the movement of the animal and count the number of rotations, and methods that indirectly detect the vibrations of the breeding cage. Methods used include detecting animal movements, directly attaching transducers such as minute accelerometers to animals to detect body movements, and creating electric or magnetic fields in breeding cages to detect minute changes in current. It is being

FIG. 1a shows an example of a method using a rotating rearing cage, and FIG. 1b shows an example of a method of attaching a transducer directly to a small animal.

In addition to the above-mentioned method of rotating the breeding cage, other methods amplify the electrical signals output from transducers and sensors, and determine the animal's activity state when the signal is larger than a certain standard. It is commercially available as an automatic analyzer for quantification and analysis. However, such devices can only measure increases and decreases in the animal's activity level, and cannot determine the detailed state of the animal when it is inactive, such as whether it is sleeping or awake and resting. I couldn't do it.

On the other hand, to determine the sleeping state of experimental animals, the three elements of the animal's brain waves, myoelectric potential, and eye movement are measured and written on recording paper, and these recorded electroencephalogram images, myoelectric potential images, and eye movement potential images are recorded. The researchers read the data and compare them with each other, and the researchers compare them with each other and read them for a unit time (10~
A method is used in which the determination is made every 30 seconds).

In general, in the case of humans, how to read recorded development waveforms is easily influenced by the subjectivity of the observer, and because a common understanding among researchers could not be achieved, an international text was created at the end of the 1960s. It was done. This shows a typical recorded image corresponding to the depth of sleep among recorded images of brain waves, myoelectric potentials, and eye movements for about 20 seconds actually measured in humans, and also describes its characteristics. This is an international agreement that states, ``Once we have obtained this level, we will express it as the level of sleep depth.'' An example of this is shown in Figure 2.

Figure 2a shows a recorded image of stage 1 sleep, and Figure 2b shows a recorded image of stage 2 sleep. In the diagram, ○...Ninroken

Claims (1)

[Claims] 1. Means for inputting the peak value for each unit time of a body movement signal detected from a small animal, and brain waves in a specific frequency band that predominantly appears during deep sleep among the brain wave signals detected from the small animal. A means for inputting the integral value of the signal in the same unit time as the body movement signal, and a function graph of the relationship between the magnitude and appearance frequency of each of the input body movement signal and brain wave signal on a coordinate axis. and means for binarizing the input body movement signal into an activity level and an inactivity level (BM ₁₁ , BM ₁₀ ) using the magnitude of the body movement signal corresponding to the minimum point of the function graph as a reference value. Then, the similarly input electroencephalogram signal is binarized into deep sleep level and non-deep sleep level using the magnitude of the integral value of the electroencephalogram signal corresponding to the minimum point of the above function graph as a reference value (D ₁₁ , D ₁₀ ) Based on these binarized body movement signals and brain wave signals, the state of the small animal per unit time is determined as the active state (BM ₁₁ , D ₁₀ , D ₁₁ ).
, a means for sequentially classifying into a deep sleep state (BM ₁₀ , D ₁₁ ) and a resting state (BM ₁₀ , D ₁₀ ) to generate a single time series data, and an input body movement signal and an electroencephalogram signal. REM, in which irregular microbody movement signals and a decrease in brain wave signals appear in synchronization for 10 to 180 seconds.
In the time-series data that includes means for detecting a sleep state and the above four states, a resting state is classified as a resting state when both the preceding and following states are active states, and a resting state in an awake phase, and a light sleep in other cases. 1. A behavioral state analysis device for a small animal, comprising means for subdividing into states. 2. Claim 1 states that the invention includes a means for extracting an active state interposed in a deep sleep state or a REM sleep state from time-series data, and identifying and classifying it as a phasic body movement state. Features: Small animal behavior analysis device.