Study on schizophrenia mouse model using automated cage monitoring system

Schizophrenia is a serious mental health condition that affects thoughts, moods, perceptions, and behaviors. Affected individuals experience positive symptoms like delusions and hallucinations, and negative symptoms like social withdrawal, cognitive deficits, disorganized thoughts and speech, and a decreased experience of pleasure. While schizophrenia is caused by a complex interplay of genetic, environmental, and lifestyle factors, precise mechanisms remain elusive.

Animal models provide valuable insights into the neurobiological mechanisms that underpin schizophrenia. However, conventional behavioral assessments require human handling and capture sensory or motor responses to specific stimuli, which may not reflect spontaneous behaviors in a naturalistic setting.

To overcome this limitation, a team of researchers led by Assistant Professor Hisayoshi Kubota, along with Professor Taku Nagai, both from the Division of Behavioral Neuropharmacology, International Center for Brain Science, Fujita Health University, Japan, employed 'IntelliCage'-an automated cage monitoring system-to assess behavioral changes in a mouse model of schizophrenia. In this system, each mouse is labeled with a unique radio frequency identification (RFID) microchip that enables individual behavior and activity tracking. Their findings were published in Volume 26, Issue 11 of the International Journal of Molecular Sciences on May 28, 2025.

\"By using IntelliCage, we established an ecologically valid platform for the comprehensive assessment of schizophrenia-like behaviors. Our work may help refine preclinical animal models of schizophrenia, enhance translational research in psychiatric disorders, and accelerate the identification of novel therapeutic targets,\" explains Dr. Kubota.

Impairment in glutamate-mediated neurotransmission has been implicated in schizophrenia. Further, blockade of N-methyl-D-aspartate (NMDA) receptors induces schizophrenia-like behaviors in humans. Mice treated with MK-801-an inhibitor of NMDA receptors-exhibit a range of schizophrenia-like behaviors, including hyperactivity, social deficits, and cognitive impairment. The researchers thus sought to examine the behavioral traits of mice repeatedly treated with MK-801 using the IntelliCage system that tracks their corner visits, nose pokes (reward-seeking behavior), and licks (water-seeking behavior).

They found that MK-801-treated mice visited the corners of the cage more frequently than control mice during the first three hours after treatment, suggesting a transient increase in hyperactivity and exploratory behavior in a new environment.

Next, the researchers evaluated emotional functions in the MK-801-treated mice by providing a sugar solution as a reward. Both MK-801-treated mice and controls licked the sugar-solution-containing bottle more frequently than the water bottle, suggesting an increased preference for the sugar solution. Thus, MK-801 treatment did not alter reward-seeking behaviors. On the other hand, on receiving water as a reward after prolonged hours of water deprivation, MK-801-treated mice visited corners containing water for significantly shorter durations than control mice. These findings suggest that while MK-801 treatment did not affect reward sensitivity, it suppressed competitive reward-seeking behavior in a grouped housing setting.

Shifting gears, the researchers examined how MK-801 treatment affects cognitive functions. The mice were deprived of water for seven consecutive days, during which they received water for three hours each day. During these three hours, they had to discriminate between diagonally positioned rewarded (with water) and non-rewarded corners. Both MK-801-treated mice and control mice showed comparable reward-seeking abilities and a similar decrease in discrimination errors. However, when the rewarded and non-rewarded corners were swapped, MK-801-treated mice took longer to adjust and exhibited delays in locating the reward. Although MK-801-treated mice were still able to seek the reward, their difficulty in adapting to the change suggested impaired cognitive flexibility, a hallmark of schizophrenia.

Overall, the IntelliCage system allows for long-term and non-invasive behavioral assessments in preclinical animal models of psychiatric diseases without the need for task/stimulus-based measurements and human interference. The experimental platform may be used in future studies to delineate molecular and circuit-level changes that induce schizophrenia-like behaviors.

Highlighting the long-term implications of their work, Dr. Kubota states, \"IntelliCage may become a standard tool in preclinical studies, offering reproducible behavioral assessments that can enhance the screening and evaluation of novel antipsychotic drugs. Ultimately, this could contribute to the development of more effective treatments for schizophrenia, thereby improving patients' quality of life.\"