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October 21, 2019 by Editorial | The Lancet Psychiatry

Of mice and mental health

Single-trial neural dynamics are dominated by richly varied movements; or, put another way, mice adorably fidget when thinking hard. This article and linked news item refer to an unexpected finding by Anne Churchland’s group from Cold Spring Harbor Laboratory, USA. When recording neural activity in mice trained to perform a specific task, the researchers noticed that activity within the cortex was dominated by neurons associated with movement, particularly movements not required for the task. This was interpreted as fidgeting in a similar way to humans drumming their fingers or tapping their feet while thinking—adorably or otherwise.

The observation was made possible by using a complex combination of video and other sensors with widefield and two-photon neuroimaging. Technological advances are enabling ever-more detailed studies of behaviour in freely moving laboratory animals, both in terms of computer tracking of movement and in the recording of neural activity. A key development has been optogenetic and chemogenetic targeting of neurons, whereby specific neuronal sub-types in defined brain regions can be turned on or off with light or chemical agents, allowing researchers to monitor the effects on behaviour.

While this all contributes to very exciting neuroscience, two key points when considering the potential clinical relevance are that these studies are done in animal models, and that they are of behaviour, not disorders or even symptoms. Churchland seemed to have been surprised by the diversity of movements associated with the time during which mice were deciding how to respond to a task, yet would probably not be surprised to see a colleague fiddling with an object while awaiting inspiration to write an Editorial. Yet, much time and funding is expended on animal models of psychiatric disorders where researchers seem to expect that altering the expression of a single gene produces a valid model of a complex condition, even when the relevant mutation (or even a single nucleotide polymorphism associated with an unknown mutation) occurs in only a small proportion of patients with the disorder in question. Arghya Mukherjee and colleagues published a recent report in Cell entitled “Long-lasting rescue of network and cognitive dysfunction in a genetic schizophrenia model”.

The abstract identified the model as LgDel+/– mice, without explaining what these are, which “exhibit [parvalbumin] PV neuron hypo-recruitment and associated chronic PV neuron plasticity together with network and cognitive deficits” and claimed: “All these deficits can be permanently rescued by chemogenetic activation of PV neurons or D2R antagonist treatments”, before concluding that “progression to disease in schizophrenia-model mice can be prevented by treatments supporting vH-mPFC PV network function during a sensitive time window late in adolescence, suggesting therapeutic strategies to prevent the outbreak of schizophrenia.”

Leaving aside the use of outbreak with its connotations of infectious disease for a disorder that has a fairly constant incidence around the world and across time, we have a summary that jumps from reversing network and cognitive deficits in a mouse to prevention of schizophrenia—a uniquely human disorder. There are useful mouse models of schizophrenia but they represent only a subset of its features, basically those known in people as negative or cognitive symptoms, and only some of those, for example, reduced social drive, loss of motivation, and inattention. They do not represent poverty of speech and thought, or positive symptoms such as hallucinations and delusions.

Psychiatry needs input from neuroscience, but that input will have greater credibility if it is reported clearly, accurately, and cautiously. The responsibility lies with authors, peer reviewers, and journal editors. With scientific articles now regularly being discussed via social media, and often going viral, it is essential that we start with plain facts, allowing some room for interpretation by news journalists and bloggers without entering the realms of hyperbole, which can only lead to disillusionment with science in the long run.

While animal models will continue to be important tools for scientists to understand the basic biology of the brain, translating that knowledge to human experiences of mental illness is complex and fraught. Translational scientists should avoid the temptation to oversimplify and oversell the potential clinical implications of their work. If they do not, they risk, like unlucky mice, searching for the cheese but getting lost in a maze.

For single-trial neural dynamics see Nat Neurosci 2019; 22: 1677–86

For mice that adorably fidget see

For the report on a genetic schizophrenia model see Cell 2019; 178: 1387–402. e14

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