Three species is better than one: multiscale, multimodal, multi‐species analyses of prefrontal cortical form, physiology and function

The increasing molecular, anatomical and temporal precision of modern neuroscientific methods continues to unveil a rich diversity of synapses, cells and brain regions. This heterogeneity spans all scales and allows the brain to adapt to the vast array of experiences, options and outcomes encountered across a lifetime. The prefrontal cortex (PFC) is typically portrayed as the pinnacle of this adaptation, a central hub of cognition able to flexibly integrate, process and route information according to external demands and internal state (Friedman & Robbins, 2022; Le Merre et al., 2021; Miller & Cohen, 2001). How do PFC inputs, cell-types and outputs mediate these complex interactions? How does PFC physiology configure and coordinate downstream circuits via top-down outputs to distributed recipients? And how do we move beyond “high-resolution phrenology” to capture the convergent features of PFC physiology required to inform both understanding and clinical and societal applications? A symposium entitled ‘Decoding Prefrontal Cortical Physiology: Circuits of Cognition’ debated these questions during the annual conference of The Physiological Society held online in the summer of 2021. This editorial summarises the symposium objectives, which centred on integrating rodent and non-human primate models to understand the connectivity, computational capabilities, and behavioural impacts of PFC circuits. A key goal was to synthesise evidence across experimental species and paradigms, identifying potential canonical features of PFC physiology and function. Two of the symposium speakers expand on these topics in detailed reviews: Alexander, Wood et al. (2023) interrogate the roles of ventromedial PFC in emotional regulation, integrating comparative evidence from mice, rats, marmosets and humans; and Perry et al. (2023) navigate the loops of cortico-thalamo-cortical interactions to highlight the importance of distributed, network information processing in cognition, cognitive impairment and future cognitive therapeutics. Both Alexander et al., and Roberts (2023) and Perry et al., and Mitchell (2023) exemplify the power of behavioural neuroscience in non-human primates. However, the symposium also harnessed the potential of mouse models to delineate the cellular and circuit mechanisms of PFC function, mapping the local and long-range connections that underpin prefrontal computations (Anastasiades & Carter, 2021) and the cortico-cortical population coding that enables flexible behaviour (Banerjee et al., 2020). It is clear that sustaining and integrating these complementary approaches across scales and species remains essential if we are to understand PFC well enough to treat the many disorders associated with its dysfunction (Chini & Hanganu-Opatz, 2021, Anastasiades, De Vivo et al., 2022).