a | The oculomotor delayed response (ODR) task is a spatial working memory task that is used to probe the physiological profiles of prefrontal cortex (PFC) neurons. The subject must remember the spatial position of the most recent cue over a delay period of several seconds and then indicate that position with a saccade to the memorized location. b | The region of the monkey dorsolateral PFC (Walker’s area 46) where neurons show persistent, spatially tuned firing during the delay period in the ODR task. c | An example of a PFC neuron that showed persistent firing during the delay period if the cue had occurred at 90° — the ‘preferred direction’ for this neuron (left middle plot) — but not if the cue appeared in a ‘non-preferred’ direction (other plots). The rasters show the firing of the neuron over seven trials at each spatial position. d | A schematic drawing of the PFC microcircuits that underlie spatial working memory as described by Goldman-Rakic40. Layer III pyramidal cells receive highly processed spatial information (represented by the green lines) from parietal association cortices. Pyramidal cells with similar spatial characteristics engage in recurrent excitation to maintain persistent activity over the delay period (note that the subcellular localization of these excitatory connections is not currently known; they could be on the apical and/or basal dendrites). GABA (γ-aminobutyric acid)-ergic interneurons, such as basket cells (B) and chandelier cells (C) help to spatially tune neurons through lateral inhibition. Inputs from cross-directional microcircuits (neurons with different tuning characteristics) are shown in grey. AS, arcuate sulcus; PS, principal sulcus. Parts a–c are modified, with permission, from REF. 60 ©(2007) Cell Press.

Both noradrenaline (NA, part a) and dopamine (DA, part b) have ‘inverted U-shaped’ influences on prefrontal cortex (PFC) physiology and cognition, whereby either too little or too much of the neurotransmitter impairs PFC function. In an oculomotor delayed response task, with optimal levels of NA or DA release under alert, non-stressed conditions (top of the curves), PFC neurons fire (as shown in the green traces) during the delay period following cues for preferred but not non-preferred directions. NA enhances delay-related firing in response to cues in preferred directions by stimulating α_2A-receptors (increasing the ‘signal’), whereas DA weakens delay-related firing in response to cues in non-preferred directions by stimulating D1 receptors (decreasing the ‘noise’). Administration of appropriate concentrations of the α_2A-receptor agonist guanfacine or the D1 receptor agonist SKF81297 also has this effect. With high levels of NA release during stress (right side of the curve), NA engages the lower-affinity α₁-receptors and so reduces neuronal firing. Similarly, excessive D1 receptor stimulation during stress suppresses cell firing. Administration of the α₁-receptor agonist phenylephrine or a high concentration of SKF81297 can mimick the effects of high NA and DA levels, respectively. In each graph, the dotted lines indicate the transition between (from left to right) the fixation period, the cue period, the delay period and the oculomotor response period.

Intracellular signalling pathways activated by stress exposure have feedforward interactions that rapidly impair prefrontal cortex (PFC) cognitive function. High levels of dopamine (DA) D1 receptor stimulation (and probably noradrenaline (NA) β₁-receptor stimulation as well) activate adenylyl cyclases (ACs) to produce cyclic AMP. cAMP opens hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN channels) on dendritic spines to produce the h current (I_h), which weakens network inputs and decreases delay-related firing. High levels of NA also stimulate α₁-receptors, which activate phosphatidylinositol biphosphate (PIP2)–protein kinase C (PKC) signalling. Subsequent inositol-1,4,5-trisphosphate (InsP₃)-mediated Ca²⁺ release has been shown to reduce PFC cell firing by opening SK channels, leading to a current (I_SK), and has been shown to maintain firing through the depolarizing current I_CAN. I_CAN can be reduced by PKC and cAMP, such that the suppressive effects of I_SK probably predominate under conditions of stress. The two signalling pathways interact to potentiate each other’s actions (dotted arrows); for example, cAMP can potentiate InsP₃-medicated Ca²⁺ release through protein kinase A-mediated phosphorylation of InsP₃ receptors. Conversely, Ca²⁺ can activate many isoforms of AC to generate more cAMP. Glucocorticoids might also activate these pathways (see main text). Enzymes that normally provide the molecular brakes on these stress signalling pathways (disrupted in schizophrenia 1 (DISC1), regulator of G-protein signalling 4 (RGS4) and DAG kinase (DGK)) are often genetically altered in families with serious mental illness, thus increasing susceptibility to stress exposure. Note that the cAMP and PKC signalling pathways have also been shown to be activated in the amygdala during stress, where they strengthen long-term memory consolidation and fear conditioning. DAG, diacyglycerol; PDE4B, phosphodiesterase 4B.

a | The efficacy of network inputs onto dendritic spines of the apical and/or basal dendrites is dynamically regulated by cyclic AMP–hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN channel) signalling. Under optimal conditions, appropriate network connections are strengthened by α_2A-receptor inhibition of cAMP–HCN channel signalling, whereas inappropriate network connections are weakened by dopamine D1 receptor activation of cAMP–HCN channel signalling. The small volume of the spine compartment probably allows very localized regulation of nearby HCN channels. The resulting specific pattern of network connectivity allows accurate representation of the cue’s spatial position in the oculomotor delayed response task, and the breadth of connectivity can be dynamically regulated based on current cognitive demands. b | HCN channels on the plasma membrane of dendritic shafts probably regulate excitability. They might not be open when the dendrite is depolarized by large numbers of excitatory network connections. c | Under optimal conditions, the cell body probably receives network signals and fires accordingly. d | Under optimal conditions the PFC shows highly patterned activity, whereby specific subsets of neurons are active to represent the precise spatial position of a stimulus. This is denoted in the figure, in which only the microcircuit representing 90° is active. Note that interneurons are not shown in this diagram for the sake of clarity. Network inputs are shown on the apical dendrites, but they might actually be on basal dendrites. Red circles represent α_2A-receptor strengthening of network inputs; grey circles represent D1 receptor–cAMP weakening of a network connection. e | Under conditions of stress, high levels of cAMP open HCN channels throughout the dendrite, weakening all network connections. f | With loss of network excitatory inputs the dendrite might hyperpolarize, and HCN channels on dendritic shafts might open to help maintain dendritic excitability. HCN channel opening would also reduce the effectiveness of inputs onto the distal portions of the dendrite. g | High levels of phosphatidylinositol signalling during stress would increase inositol-1,4,5-trisphosphate (InsP₃)-mediated waves of intracellular Ca²⁺ release. When the Ca²⁺ waves invade the soma, they open small-conductance, Ca²⁺-activated K⁺ channels (SK channels) and reduce cell firing. h | Under stressful conditions, network connections are weakened (grey circles) and, as a result, network firing is reduced and unpatterned. Thus, prefrontal cortex neurons are unable to accurately represent information in working memory. Unpatterned, generalized activity might serve another function — for example, stimulating stress pathways in the brainstem.

The prefrontal cortex (PFC) has extensive connections with other cortical and subcortical regions that are organized in a topographical manner, such that regions that regulate emotion are situated ventrally and medially (green area in part a of the figure) and regions that regulate thought and action are situated more dorsally and laterally (blue and blue–green areas in part a). The dorsolateral PFC (DLPFC) has extensive connections with sensory and motor cortices and is key for regulating attention, thought and action163. In humans, the right inferior PFC (rIPFC) seems to be specialized for inhibiting inappropriate motor responses4. By contrast, the ventromedial PFC (VMPFC) has extensive connections with subcortical structures (such as the amygdala, the nucleus accumbens and the hypothalamus) that generate emotional responses and habits164–166 and is thus able to regulate emotional responses. Finally, the dorsomedial PFC (DMPFC) has been associated with error monitoring9 and, in human functional MRI studies, reality testing167. These PFC regions extensively interconnect to regulate higher-order decision making and to plan and organize for the future. Under non-stress conditions (see part a of the figure), the extensive connections of the PFC orchestrate the brain’s activity for intelligent regulation of behaviour, thought and emotion. The PFC also has direct and indirect connections to monoamine cell bodies in the brainstem, such as the locus coeruleus (LC) (where noradrenaline projections arise) and the substantia nigra (SN) and ventral tegmental area (VTA) (where the major dopamine projections originate), and thus can regulate its own catecholamine inputs. Optimal levels of catecholamine release in turn enhance PFC regulation, thus creating a ‘delicious cycle’. Under conditions of psychological stress (see part b of the figure) the amygdala activates stress pathways in the hypothalamus and brainstem, which evokes high levels of noradrenaline (NA) and dopamine (DA) release. This impairs PFC regulation but strengthens amygdala function, thus setting up a ‘vicious cycle’. For example, high levels of catecholamines, such as occur during stress, strengthen fear conditioning mediated by the amygdala168. By contrast, stress impairs higher-order PFC abilities such as working memory and attention regulation. Thus, attention regulation switches from thoughtful ‘top-down’ control by the PFC that is based on what is most relevant to the task at hand to ‘bottom-up’ control by the sensory cortices, whereby the salience of the stimulus (for example, whether it is brightly coloured, loud or moving) captures our attention5. The amygdala also biases us towards habitual motor responding rather than flexible, spatial navigation14. Thus, during stress, orchestration of the brain’s response patterns switches from slow, thoughtful PFC regulation to the reflexive and rapid emotional responses of the amygdala and related subcortical structures.