In the early 1990s, the small GTPases Rho and Rac were discovered to be major regulators of the actin cytoskeleton in mammalian fibroblasts. Cell division cycle 42 (Cdc42), another member of the Rho GTPase family, was also identified as a key regulator of polarized growth during yeast budding. These classic studies¹ led to the hypothesis that Rho GTPases are central players in the regulation of the morphogenesis of axons and dendrites in neurons². Indeed, this hypothesis was borne out by studies using dominant mutants — from insect to mammalian neurons — that supported the idea of an integral role for Rho GTPases in axonal, dendritic and spine morphogenesis. Given their central positions in intracellular signalling, Rho GTPases are poised to mediate the crucial link between extracellular factors that regulate the growth and guidance of neuronal processes, and the actin cytoskeleton. The 2000 Review published in this journal³ summarized the state of the field a decade ago, examining the neuronal morphogenetic processes that Rho GTPases regulate and the mechanisms by which Rho GTPases link upstream regulators to downstream cytoskeletal elements.

Over the last decade, the study of brain function has witnessed a pivotal change of focus from investigating the localization of specialized brain areas to investigation of spatially distributed functional networks. Our Review, published in this journal¹¹, was to become a hallmark of this paradigm shift. With something of a lucky prediction we entitled our paper `The brainweb' not knowing that, 10 years later, the development of internet 2.0, web dynamics and small-world network theories would, more than ever, justify this title.

Attention is the mind's ability to focus on what is important (stimuli, thoughts, memories). An important early insight into the neural mechanisms of attention was the recognition that there is a separation between sources of attention — that is, dedicated neural systems for controlling information flow²⁷ — and the sites at which attention modulates sensory input, such as the visual cortex. Neural recordings in monkeys in the 1980s to 1990s emphasized the dorso lateral prefrontal cortex as the main source of attention²⁸. However, beginning in the early 1990s, human neuroimaging studies showed that a different set of regions, more dorsally located in the frontal and posterior parietal cortex, were consistently recruited under conditions in which subjects selected the location or features of stimuli or the motor response relevant to a task, suggesting that these regions are an important source of attention. Our 2002 Review²⁹ highlighted the convergent evidence from neurophysiological, neuropsychological and neuroimaging observations that indicated the importance of a bilateral dorsal frontoparietal network as a source of goal-driven stimulus–response selection. We also introduced a second, ventral frontoparietal network that is lateralized to the right hemisphere and that is driven by the detection of stimuli, especially when stimuli are unattended (FIG. 1). The existence and function of this network were more speculative, particularly as little supporting evidence was available from the literature on monkeys. We were encouraged, however, by the anatomical overlap between the ventral network and lesions causing spatial neglect — a syndrome characterized by spatial and non-spatial deficits. We suggested, and later confirmed^30,31, that neglect reflects the combined dysfunction of both attention networks, with the ventral network being directly damaged by stroke and the dorsal network becoming impaired by disconnection from ventral regions.

The discovery of the endogenous cannabinoid system challenged conventional views about chemical neurotransmission. The main components of this system — a class of lipid molecules that mimic Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in marijuana — serve key functions in the regulation of synaptic activity, yet they eschew some of the most basic rules of neurotransmission. The compounds, called endocannabinoids, are not stored in synaptic vesicles and do not transmit information from presynaptic to postsynaptic neurons, as most transmitters do. Rather, they are made on demand in membranes of postsynaptic cells and intervene in retrograde signalling processes in which information about postsynaptic activity flows back to nerve terminals.

In his classic work The Wisdom of the Body, the renowned physiologist Walter Cannon marvelled that:

somehow the unstable stuff of which we are composed has learned the trick of maintaining stability.⁵⁰

This trick is nowhere more astonishing than in the CNS where, somehow, despite their astronomical complexity, the circuits within our brains wire themselves up during development and manage to generate stable activity patterns throughout our lives. Although Claude Bernard and Walter Cannon (the `fathers of homeostasis') long ago enshrined homeostatic regulation of key physiological parameters as a central tenet of physiology, it took a surprisingly long time for neurophysiologists to apply this thinking systematically to the understanding of neural circuits. Over the past roughly 15 years this has changed dramatically with the demonstration that neuronal firing is itself a key physiological parameter that is subject to homeostatic regulation and with the discovery of a family of homeostatic plasticity mechanisms that together keep neuronal firing within functional boundaries⁵¹. These include the regulation of intrinsic neuronal excitability through the modulation of ion channel number and function⁵² and the homeostatic regulation of synaptic strengths^51,53. Our 2004 Review⁵¹ came at a key moment for this nascent field and — by suggesting that homeostatic mechanisms are essential for proper circuit function — has played an inspirational role in driving research over the past 6 years.

The message of our Review in 2005 (^{REF. 60}) was twofold. Firstly, we argued that stress hormones, such as corticosteroids, coordinate responses of the body and the brain to achieve behavioural adaptation in the light of a stressful experience. These coordinated actions take place via two closely related nuclear receptor types, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), localized in brain regions that are implicated in cognitive processing and emotional responses. Secondly, we proposed that an imbalance in these receptor-mediated actions renders predisposed individuals more vulnerable to mental disorders, such as major depression. Since then, major progress has been made in three fields: the molecular and cellular underpinnings of corticosteroid actions, functional connectivity underlying behavioural adaptation and identification of factors that may tip the balance from resilience to vulnerability in stress-related psychopathology.

At the time of our Review⁷³, several studies had observed unique activations in medial prefrontal cortex (mPFC) regions in individuals when making judgments about people and their thoughts. Although researchers speculated that the mPFC might represent a special module for social cognition, the specific psychological processes represented by these activations were unclear.

Microglia, the resident innate immune cells in the brain, are strongly implicated as a source of neuropathology in neurodegenerative diseases. Our 2007 Review⁷⁹ was designed to delineate the mechanisms that are responsible for microglia-mediated neurotoxicity, and in it we presented evidence that microglia cause neuronal death when they are chronically activated⁷⁹. Specifically, we detailed the many, diverse triggers of microglial activation (for example, environmental toxins, endogenous disease proteins and neuronal damage) that converge onto a common neurotoxic pathway in microglia: reactive microgliosis and the chronic production of reactive oxygen species⁷⁹. In neurotoxic reactive microgliosis, the microglial response to neuronal injury culminates in a chronic, self-propelling cycle that fuels further neuronal damage and consequent microglial activation. This process has been emphasized as a common underlying factor in many neurodegenerative conditions.

The concept that the immune system talks to the brain to regulate a variety of behaviours was reinforced and extended in our Review published in 2008 (^{REF. 96}). This article helped to solidify the concept that during a peripheral inflammatory event, the immune system subjugates the brain and holds it captive until the infection is cleared. There is nothing pathological about this because it is as important for the survival of the host as is the fear response to a dangerous threat. All this was already known when our Review was published⁹⁷. The true contribution of our Review was to go one step further, to propose a mechanism that could explain how a normally adaptive sickness response to a danger signal sensed by the immune system can go awry and lead to psychopathology in the form of major depressive disorders. At that time, systemic inflammation had already been identified as a possible causal factor in the development of major depressive disorders^98,99. However, clinical depression was viewed as simply a more prolonged and intense variant of sickness behaviour. We challenged this idea by proposing that although inflammation-induced depression develops on a background of sickness behaviour, the two conditions are different. Depression is mediated by a mechanism other than just the expression and action of proinflammatory cytokines in the brain. The molecular switch that promotes the transition from sickness to depression is activation of the tryptophan degrading enzyme, indoleamine 2,3-dioxygenase (IDO). This enzyme normally mediates the development of immunotolerance and resolution of an immune response by causing depletion of tryptophan from the local milieu and by producing cytotoxic metabolites, such as quinolinic acid¹⁰⁰. However, activation of the IDO pathway in the brain in response to a systemic immune response can lead to accumulation of neurotoxic metabolites, probably as a result of microglial and/or endothelial cell activation. Since our Review was published, a substantial amount of experimental evidence supporting a role for tryptophan metabolites in the pathophysiology of depression has accumulated^101,102. Once more, the concept itself was not totally new¹⁰³. However, the idea gained respectability because it has been tested in appropriate experimental designs in which sickness and depression-like behaviour can be dissociated.

The most cited article in Nature Reviews Neuroscience in 2009 was a Perspective in which I presented a succinct overview of an extraordinary convergence of recent findings across widely disparate fields of neuroscience. I proposed that these findings support the hypothesis that the (right and left) anterior insula engenders human subjective awareness¹⁰⁶. The Perspective is cited frequently because this novel viewpoint provides a cogent and appealing explanation for the unexpected activation of the anterior insula (and the anterior cingulate) that investigators have reported in hundreds of functional imaging studies. The groundwork for this view was laid by a 2002 Perspective article, also highly cited¹⁰⁷, in which I described a phylogenetically novel pathway to the primate insular cortex that provides a homeostatic sensory representation of the physiological condition of the body, and that leads to re-representations in the anterior insula that underlie human awareness of affective feelings, consistent with the James–Lange theory of emotion¹⁰⁸ and the `somatic marker' hypothesis¹⁰⁹. The 2009 Perspective¹⁰⁶ suggested, based on recent neuroimaging findings, that this pathway involves an evolutionary progression of increasingly energy-efficient homeostatic re-representations extending from the posterior to anterior insula that successively incorporate all neural activity, an idea that is consistent with the social brain hypothesis¹¹⁰ and the recognition that energy utilization is a crucial arbiter of brain evolution¹¹¹.