Humans share with many species a non-verbal system to estimate absolute quantity. This sense of number has been linked to the activity of quantity-selective neurons that respond maximally to preferred numerosities. With functional magnetic resonance imaging adaptation, we now show that populations of neurons in the human parietal and frontal cortex are also capable of encoding quantity ratios, or proportions, using the same non-verbal analog code as for absolute number. Following adaptation to visually presented constant proportions (specified by the ratio of line lengths or numerosities), we introduced novel relative magnitudes to examine the tuning characteristics of the population of stimulated neurons. In bilateral parietal and frontal cortex we found that blood oxygenation level-dependent signal recovery from adaptation was a function of numerical distance between the deviant proportion and the adaptation stimulus. The strongest effects were observed in the cortex surrounding the anterior intraparietal sulcus, a region considered pivotal for the processing of absolute magnitudes. Overall, there was substantial overlap of frontoparietal structures representing whole numbers and proportions. The identification of tuning to non-symbolic ratio stimuli, irrespective of notation, adds to the magnitude system a remarkable level of sophistication by demonstrating automatic access to a composite, derived quantitative measure. Our results argue that abstract concepts of both absolute and relative number are deeply rooted in the primate brain as fundamental determinants of higher-level numerical cognition.

Prefrontal cortex (PFC) and posterior parietal cortex are important for maintaining behaviorally relevant information in working memory. Here, we challenge the commonly held view that suppression of distractors by PFC neurons is the main mechanism underlying the filtering of task-irrelevant information. We recorded single-unit activity from PFC and the ventral intraparietal area (VIP) of monkeys trained to resist distracting stimuli in a delayed-match-to-numerosity task. Surprisingly, PFC neurons preferentially encoded distractors during their presentation. Shortly after this interference, however, PFC neurons restored target information, which predicted correct behavioral decisions. In contrast, most VIP neurons only encoded target numerosities throughout the trial. Representation of target information in VIP was the earliest and most reliable neuronal correlate of behavior. Our data suggest that distracting stimuli can be bypassed by storing and retrieving target information, emphasizing active maintenance processes during working memory with complementary functions for frontal and parietal cortex in controlling memory content.

Although the concept of whole numbers is intuitive and well suited for counting and ordering, it is with the invention of fractions that the number system gained precision and flexibility. Absolute magnitude is encoded by single neurons that discharge maximally to specific numbers. However, it is unknown how the ratio of two numbers is represented, whether by processing numerator and denominator in separation, or by extending the analog magnitude code to relative quantity. Using functional MRI adaptation, we now show that populations of neurons in human fronto-parietal cortex are tuned to preferred fractions, generalizing across the format of presentation. After blood oxygen level-dependent signal adaptation to constant fractions, signal recovery to deviant fractions was modulated parametrically as a function of numerical distance between the deviant and adaptation fraction. The distance effect was invariant to changes in notation from number to word fractions and strongest in the anterior intraparietal sulcus, a key region for the processing of whole numbers. These findings demonstrate that the human brain uses the same analog magnitude code to represent both absolute and relative quantity. Our results have implications for mathematical education, which may be tailored to better harness our ability to access automatically a composite quantitative measure.

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The lateral prefrontal cortex (PFC), a hub of higher-level cognitive processing, is strongly modulated by midbrain dopamine (DA) neurons. The cellular mechanisms have been comprehensively studied in the context of short-term memory, but little is known about how DA regulates sensory inputs to PFC that precede and give rise to such memory activity. By preparing recipient cortical circuits for incoming signals, DA could be a powerful determinant of downstream cognitive processing. Here, we tested the hypothesis that prefrontal DA regulates the representation of sensory signals that are required for perceptual decisions. In rhesus monkeys trained to report the presence or absence of visual stimuli at varying levels of contrast, we simultaneously recorded extracellular single-unit activity and applied DA to the immediate vicinity of the neurons by micro-iontophoresis. We found that DA modulation of prefrontal neurons is not uniform but tailored to specialized neuronal classes. In one population of neurons, DA suppressed activity with high temporal precision but preserved signal/noise ratio. Neurons in this group had short visual response latencies and comprised all recorded narrow-spiking, putative interneurons. In a distinct population, DA increased excitability and enhanced signal/noise ratio by reducing response variability. These neurons had longer visual response latencies and were composed exclusively of broad-spiking, putative pyramidal neurons. By gating sensory inputs to PFC and subsequently strengthening the representation of sensory signals, DA might play an important role in shaping how the PFC initiates appropriate behavior in response to changes in the sensory environment.

All neuronal circuits are subject to neuromodulation. Modulatory effects on neuronal processing and resulting behavioral changes are most commonly reported for higher order cognitive brain functions. Comparatively little is known about how neuromodulators shape processing in sensory brain areas that provide the signals for downstream regions to operate on. In this article, we review the current knowledge about how the monoamine neuromodulators serotonin, dopamine and noradrenaline influence the representation of sensory stimuli in the mammalian sensory system. We review the functional organization of the monoaminergic brainstem neuromodulatory systems in relation to their role for sensory processing and summarize recent neurophysiological evidence showing that monoamines have diverse effects on early sensory processing, including changes in gain and in the precision of neuronal responses to sensory inputs. We also highlight the substantial evidence for complementarity between these neuromodulatory systems with different patterns of innervation across brain areas and cortical layers as well as distinct neuromodulatory actions. Studying the effects of neuromodulators at various target sites is a crucial step in the development of a mechanistic understanding of neuronal information processing in the healthy brain and in the generation and maintenance of mental diseases.

Flexibly applying abstract rules is a hallmark feature of executive functioning represented by prefrontal cortex (PFC) neurons. Prefrontal networks are regulated by the neuromodulator dopamine, but how dopamine modulates high-level executive functions remains elusive. In monkeys performing a rule-based decision task, we report that both dopamine D1 and D2 receptors facilitated rule coding of PFC neurons, albeit by distinct physiological mechanisms. Dopamine D1 receptor stimulation suppressed neuronal firing while increasing responses to the preferred rule, thereby enhancing neuronal rule coding. D2 receptor stimulation, instead, excited neuronal firing while suppressing responses to the nonpreferred rule, thus also enhancing neuronal rule coding. These findings highlight complementary modulatory contributions of dopamine receptors to the neuronal circuitry mediating executive functioning and goal-directed behavior.

Ca2ϩ signals in neurons use specific temporal and spatial patterns to encode unambiguous information about crucial cellular functions. To understand the molecular basis for initiation and propagation of inositol 1,4,5-trisphosphate (InsP 3 )-mediated intracellular Ca 2ϩ signals, we correlated the subcellular distribution of components of the InsP 3 pathway with measurements of agonist-induced intracellular Ca 2ϩ transients in cultured rat hippocampal neurons and pheochromocytoma cells. We found specialized domains with high levels of phosphatidylinositol-4-phosphate kinase (PIPKI␥) and chromogranin B (CGB), proteins acting synergistically to increase InsP 3 receptor (InsP 3 R) activity and sensitivity. In contrast, Ca 2ϩ pumps in the plasma membrane (PMCA) and sarco-endoplasmic reticulum as well as buffers that antagonize the rise in intracellular Ca 2ϩ were distributed uniformly. By pharmacologically blocking phosphatidylinositol-4-kinase and PIPKI␥ or disrupting the CGB-InsP 3 R interaction by transfecting an interfering polypeptide fragment, we produced major changes in the initiation site and kinetics of the Ca 2ϩ signal. This study shows that a limited number of proteins can reassemble to form unique, spatially restricted signaling domains to generate distinctive signals in different regions of the same neuron. The finding that the subcellular location of initiation sites and protein microdomains was cell type specific will help to establish differences in spatiotemporal Ca 2ϩ signaling in different types of neurons.