To what extent can we use mice to accurately represent the human mind? Photo credit: Nikolett Emmert via Unsplash
The complex puzzle of psychiatric research
Can a mouse hallucinate? A strange question, maybe even philosophical, but not a pointless one. In 2019, the World Health Organisation reported that one in every eight people (that is almost 1 billion people worldwide) are affected by a mental disorder, including schizophrenia, depression, bipolar, and autism spectrum disorder. Antipsychotic drugs and psychotherapy represent the first line of treatment for most of these disorders, offering relief for some individuals but with inconsistent results that rarely lead to curative outcomes. Medications often target symptoms rather than underlying causes and are frequently accompanied by a range of side effects, from weight gain to emotional blunting and motor disturbances. For many, the experience of taking psychiatric medication is not just a medical challenge, but a social and emotional one. The stigma surrounding psychiatric disorders and the treatments used to manage them can lead to shame and a reluctance to seek help in the first place.
You can image a tumour or culture a virus but how do you measure a delusion?
Such challenges point to a deeper issue: the human brain is locked in a skull, and most of its (dys)functions, particularly psychiatric ones, are invisible to the naked eye—rendering them notoriously difficult to study. Clinical investigations have been instrumental in elucidating anatomical and functional brain alterations that commonly characterise psychiatric conditions. In parallel, powerful large-scale genome sequencing techniques have allowed the identification of multiple gene mutations significantly associated with high risk of developing psychiatric disorders. However, despite these major advances in our understanding of psychiatric disorders, the underlying neurobiological mechanisms remain largely unknown, significantly contributing to the long stagnation in the discovery of novel therapeutic targets. For decades, researchers have attempted to uncover the etiology of psychiatric disorders, but these remain some of the least understood conditions in medicine. You can image a tumour or culture a virus but how do you measure a delusion? How do you model one’s subjective experience of the world?
This is where mice come in.
Rodents at the frontline of psychiatry
Studies in animals, and particularly rodents, have been instrumental in some of the biggest breakthroughs in medical history: from antibiotics and organ transplantation to the polio vaccine, and the use of insulin for diabetes. In the field of psychiatric research however, the relevance of animal models remains a topic of debate. After all, how much can a mouse really teach us about the human mind?
Despite these doubts, it is well established that mice share striking similarities with humans at the genomic level (~90% preserved genomic order between both species) and general brain organisation. Scientists leverage these shared features as an entry point into the brain’s complex wiring system to directly explore the neurobiological foundations of cognition and behaviour. Genetic engineering and pharmacological manipulations are coupled with powerful state-of-the-art tools (including in vivo electrophysiological recordings, imaging techniques, and behavioural paradigms) to study brain processes relevant to psychiatric disorders and the neuronal circuits that underlie them. It is important to stress however that through this preclinical approach, modern psychiatric research does not aim to create a “schizophrenic” or “bipolar” mouse, but rather to model psychiatric disorders at the level of neuronal activity and behaviour in ways that could not be implemented in humans.
Measuring the invisible
In general, preclinical psychiatric research strategy unfolds in two complementary directions. First, researchers use mice that have not undergone any genetic modification to probe brain processes which are commonly disrupted in psychiatric disorders, in order to identify their neurobiological substrates. Processes such as working memory, decision-making, and even social interactions can be studied at the level of neuronal activity using carefully designed and robust behavioural paradigms.
A strong example comes from a recent study published in Science which demonstrated that mice exhibit hallucination-like perception. In an elegant behavioural task, mirroring those used in humans, mice were trained to report the presence of a faint tone signal embedded in background noise. Confidence in that decision was inferred through the amount of time mice were willing to wait for a reward. Strikingly, mice reported hearing a tone with high confidence in ~16% of trials where no signal was actually presented, a phenomenon the authors termed a “hallucination-like percept”. Importantly, the study went on to reveal that the occurrence of these “hallucination-like percepts” increased under conditions known to promote hallucinations in humans, such as ketamine administration or heightened expectation of a signal (achieved through varying the proportion of signal versus no-signal trials). Using genetically-engineered dopamine sensors and fibre photometry (a technique that allows real-time monitoring of fluorescent signal fluctuations in the brain) researchers discovered that elevations in dopamine levels preceded “hallucination-like percepts”. These dopamine changes were recorded in the striatum, a brain region widely implicated in both reward and perceptual processing. Crucially, increasing dopamine release in a specific subregion of the striatum increased hallucination-like behaviour, and this increase was subsequently reversed by haloperidol—a dopamine receptor antagonist. These findings strongly suggest that hallucinations (an abstract sensory phenomenon long thought to be beyond the reach of animal models) can be deconstructed into neural computations and measurable behaviour in rodents. This allows a novel entry point to unravelling the neurobiological mechanisms of perception and behaviour. However, it is crucial to point out that modelling isolated symptoms or cognitive processes in animals captures only a fraction of the multidimensional nature of psychiatric disorders in humans. Nevertheless, this fundamental research is invaluable in paving the way for a more nuanced understanding of how specific brain circuit dysfunctions can give rise to particular symptoms, and in doing so, helps push the field toward more targeted and mechanism-based interventions.
These findings strongly suggest that hallucinations can be deconstructed into neural computations and measurable behaviour in rodents.
Bridging the gap between genes and symptoms
The second path in preclinical psychiatric research starts from the top down; researchers build on findings from large-scale genetic studies to develop animal models that contain DNA mutations associated with increased risk for psychiatric disorders in humans. This approach relies on the fact that most psychiatric conditions, including schizophrenia, autism spectrum disorder, and bipolar disorder, have a strong genetic component. Genome-wide association studies and whole-exome sequencing have allowed the identification of hundreds of risk genes, and advances in genetic engineering now allow researchers to introduce these same mutations in mice. By observing how these genetic alterations affect brain development, neuronal activity, and behaviour, researchers can trace and disentangle the path from gene to phenotype.
A recent example comes from a study published in Neuron which investigated mice with a mutation in the SETD1A gene, one of the most well-replicated genetic risk factors for schizophrenia in humans. SETD1A encodes a histone methyltransferase involved in the epigenetic regulation of gene expression. The study showed that SETD1A mutant mice exhibit a range of schizophrenia-related phenotypes, including disrupted neuronal axonal branching, enhanced excitability of prefrontal cortex neurons, and behavioural deficits in a working memory task. Importantly, the authors demonstrated that pharmacological inhibition of LSD1 in adulthood (a histone demethylase that counteracts SETD1A function) results in amelioration of the effects of SETD1A deficiency; a complete restoration of the axonal arborization deficits and a full rescue of the behavioral abnormalities in working memory. These findings strongly suggest that epigenetic modulation in adulthood can rescue cognitive impairments of a developmental origin, highlighting a potential therapeutic avenue for individuals with schizophrenia. Preclinical studies like this one provide critical insights into the neurobiological mechanisms of schizophrenia and reflect the growing momentum in psychiatric research towards genetically informed therapies grounded in mechanistic insights from animal models. Indeed, this study was instrumental in informing clinical research; in 2020 a clinical study was announced to evaluate an LSD1 inhibitor, Vafidemstat, for the treatment of schizophrenia patients harboring inherited mutations in SETD1A. This study is part of a broader precision medicine approach in psychiatry, which is exploring drug applications in genetically defined subpopulations. Although these developments are promising, it is important to note that as of 2025, Vafidemstat remains in the clinical trial phase, and its efficacy and safety profiles are still under investigation. The road from preclinical findings to clinical success is long and complex, and further research is necessary to determine the therapeutic potential of LSD1 inhibitors in treating schizophrenia.
The key to understanding what makes us human
Overall, preclinical psychiatric studies underscore the power of mouse models in tracing the path from gene to circuit to behaviour and informing targeted interventions. Research in rodents has been vital in demonstrating that psychiatric symptomatology can be broken down into a chain of neuronal events that can be studied and at times, corrected. Still, this approach raises difficult questions. Can deeply subjective human experiences ever be meaningfully captured in the behaviour of a mouse? And what are the limits of translating neuronal substrates of symptoms into effective treatments?
At the heart of modern psychiatric neuroscience lies a deep paradox; we use mice, creatures so far removed from us in language and consciousness, to understand the neurobiological mechanisms underlying some of the most human aspects of ourselves, from cognition to our sense of reality.
The risk of reductionism looms large; treating psychiatric disorders as a set of disrupted genes and neuronal circuits rather than a lived experience shaped by context, culture, and individuality. Yet to dismiss animal models on the grounds that they are incomplete would be to overlook their immense value. Rather than trivialising the human mind, preclinical psychiatric research allows us to illuminate its biological roots, making visible what has long been invisible. At the heart of modern psychiatric neuroscience lies a deep paradox; we use mice, creatures so far removed from us in language and consciousness, to understand the neurobiological mechanisms underlying some of the most human aspects of ourselves, from cognition to our sense of reality. In the end, the question is not merely whether a mouse can hallucinate. It’s whether, by studying the mouse, we can better understand that which makes us human.
