Highlights d Single neurons in the human medial temporal lobe (MTL) encode numerical information ... more Highlights d Single neurons in the human medial temporal lobe (MTL) encode numerical information d Numerosity and abstract numerals are encoded by distinct neuronal populations d Numerosity representation shows a distance effect; numerals are encoded categorically d Representation of symbolic numerals may evolve from numerosity representations
The ongoing activity of prefrontal neurons after a stimulus has disappeared is considered a neuro... more The ongoing activity of prefrontal neurons after a stimulus has disappeared is considered a neuronal correlate of working memory. It depends on the delicate but poorly understood interplay between excitatory glutamatergic and inhibitory GABAergic receptor effects. We administered the NMDA receptor antagonist MK-801 and the GABA(A) receptor antagonist Bicuculline methiodide while recording cellular activity in prefrontal cortex of male rhesus monkeys performing a delayed decision task requiring working memory. The blockade of GABA(A) receptors strongly improved the selectivity of the neurons' delay activity, causing an increase in signal to noise ratio during working memory periods as well as an enhancement of the neurons' coding selectivity. The blockade of NMDA-receptors resulted in a slight enhancement of selectivity and encoding capacity of the neurons. Our findings emphasize the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.
Highlights d Stimulation of dopamine receptors enhances sensory sensitivity of PFC neurons d Stim... more Highlights d Stimulation of dopamine receptors enhances sensory sensitivity of PFC neurons d Stimulation of D1Rs and D2Rs increases signal-to-noise ratio d Neither D1R nor D2R stimulation affects the neurons' tuning sharpness d Dopamine provides a gating signal to enable access of sensory information to PFC
How is neuronal activity across distant brain regions orchestrated to allow multiple stimuli to b... more How is neuronal activity across distant brain regions orchestrated to allow multiple stimuli to be stored together in working memory, yet maintained separate for individual readout and protection from distractors? Using paired recordings in the prefrontal and parietal cortex of monkeys discriminating numbers of items (numerosities), we found that working memory content is structured by frequency-specific oscillatory synchrony. Parieto-frontal signaling in the beta band carried information about the most recent numerical input. Fronto-parietal coupling in the theta band differentiated between multiple memorized numerosities. Task-relevant and distracting stimuli were nested in spiking activity of single prefrontal neurons, but could be separated by reading out spikes at distinct phases of parietal theta oscillations. The strength of phase-locked, cross-regional memory coding predicted task performance. Frequency-specific communication channels in the fronto-parietal network could ena...
Neural oscillations in distinct frequency bands in the prefrontal cortex (pFC) are associated wit... more Neural oscillations in distinct frequency bands in the prefrontal cortex (pFC) are associated with specialized roles during cognitive control. How dopamine modulates oscillations to structure pFC functions remains unknown. We trained macaques to switch between two numerical rules and recorded local field potentials from pFC while applying dopamine receptor targeting drugs using microiontophoresis. We show that the D1 and D2 family receptors (D1Rs and D2Rs, respectively) specifically altered internally generated prefrontal oscillations, whereas sensory-evoked potentials remained unchanged. Blocking D1Rs or stimulating D2Rs increased low-frequency theta and alpha oscillations known to be involved in learning and memory. In contrast, only D1R inhibition enhanced high-frequency beta oscillations, whereas only D2R stimulation increased gamma oscillations linked to top-down and bottom-up attentional processing. These findings suggest that dopamine alters neural oscillations relevant for e...
Quantitative features of stimuli may be ordered along a magnitude continuum, or line. Magnitude r... more Quantitative features of stimuli may be ordered along a magnitude continuum, or line. Magnitude refers to parameters of different types of stimulus properties. For instance, the frequency of a sound relates to sensory and continuous stimulus properties, whereas the number of items in a set is an abstract and discrete property. In addition, within a stimulus property, magnitudes need to be processed not only in one modality, but across multiple modalities. In the sensory domain, for example, magnitude applies to both to the frequency of auditory sounds and tactile vibrations. Similarly, both the number of visual items and acoustic events constitute numerical quantity, or numerosity. To support goal-directed behavior and executive functions across time, magnitudes need to be held in working memory, the ability to briefly retain and manipulate information in mind. How different types of magnitudes across multiple modalities are represented in working memory by single neurons has only recently been explored in primates. These studies show that neurons in the frontal lobe can encode the same magnitude type across sensory modalities. However, while multimodal sensory magnitude in relative comparison tasks is represented by monotonically increasing or decreasing response functions ("summation code"), multimodal numerical quantity in absolute matching tasks is encoded by neurons tuned to preferred numerosities ("labeled-line code"). These findings indicate that most likely there is not a single type of cross-modal workingmemory code for magnitudes, but rather a flexible code that depends on the stimulus dimension as well as on the task requirements.
Neurons in the avian nidopallium caudolaterale (NCL), an endbrain structure that originated indep... more Neurons in the avian nidopallium caudolaterale (NCL), an endbrain structure that originated independently from the mammalian neocortex, process visual numerosities. To clarify the code for number in this anatomically distinct endbrain area in birds, neuronal responses to a broad range of numerosities were analyzed. We recorded single-neuron activity from the NCL of crows performing a delayed match-to-sample task with visual numerosities as discriminanda. The responses of Ͼ20% of randomly selected neurons were modulated significantly by numerosities ranging from one to 30 items. Numerosity-selective neurons showed bell-shaped tuning curves with one of the presented numerosities as preferred numerosity regardless of the physical appearance of the items. The resulting labeled-line code exhibited logarithmic compression obeying the Weber-Fechner law for magnitudes. Comparable proportions of selective neurons were found, not only during stimulus presentation, but also in the delay phase, indicating a dominant role of the NCL in numerical working memory. Both during sensory encoding and memorization of numerosities in working memory, NCL activity predicted the crows' number discrimination performance. These neuronal data reveal striking similarities across vertebrate taxa in their code for number despite convergently evolved and anatomically distinct endbrain structures.
based on largely distributed coding by single neurons that are anatomically intermingled within t... more based on largely distributed coding by single neurons that are anatomically intermingled within the same cortical area.
Working memory is associated with persistent activity in the prefrontal cortex (PFC). The neuromo... more Working memory is associated with persistent activity in the prefrontal cortex (PFC). The neuromodulator dopamine, which is released by midbrain neurons projecting into the frontal lobe, influences PFC neurons and networks via the dopamine D1 (D1R) and the D2 receptor (D2R) families. Although behavioral, clinical and computational evidence suggest an involvement of D2Rs in working memory, a neuronal explanation is missing. We report an enhancement of persistent working memory responses of PFC neurons after iontophoretically stimulating D2Rs in monkeys memorizing the number of items in a display. D2R activation improved working memory representation at the population level and increased population dynamics during the transition from visual to mnemonic representations. Computational modeling suggests that D2Rs act by modulating interneuron-to-pyramidal signaling. By increasing the population's response dynamics, D2Rs might put PFC networks in a more flexible state and enhance the neurons' working memory coding, thereby controlling dynamic cognitive control.
The prefrontal cortex (PFC) is crucial for maintaining relevant information in working memory and... more The prefrontal cortex (PFC) is crucial for maintaining relevant information in working memory and resisting interference. PFC neurons are strongly regulated by dopamine, but it is unknown whether dopamine receptors are involved in protecting target memories from distracting stimuli. We investigated the prefrontal circuit dynamics and dopaminergic modulation of targets and distractors in monkeys trained to ignore interfering stimuli in a delayed-match-to-numerosity task. We found that dopamine D1 receptors (D1Rs) modulate the recovery of task-relevant information following a distracting stimulus. The direction of modulation is cell-type-specific: in putative pyramidal neurons, D1R inhibition enhances and D1R stimulation attenuates coding of the target stimulus after the interference, while the opposite pattern is observed in putative interneurons. Our results suggest that dopaminergic neuromodulation of PFC circuits regulates mental representations of behaviourally relevant stimuli t...
Numbers that relate to the empirical property of 'rank' in a sequence (for example, 'fifth place'... more Numbers that relate to the empirical property of 'rank' in a sequence (for example, 'fifth place'). Nominal numbers Strictly linguistic labels to identify objects (for example, 'Bus number 5'). Number estimation (Also known as the analogue magnitude system and the analogue number system). A process of representing small and large set sizes that becomes systematically less precise with increasing numbers. Thus, number estimation obeys Weber's law. Subitizing (Also known as object file representation or object tracking system). The rapid tracking for up to approximately four items by assigning 'files' or 'pointers' to individual items.
Highlights d VIP neurons encode empty sets more as a distinct, nonnumerical category d In contras... more Highlights d VIP neurons encode empty sets more as a distinct, nonnumerical category d In contrast, PFC cells integrate empty sets in the numerical continuum d Prefrontal encoding of empty sets is more abstract and behaviorally relevant d Empty sets are translated into an abstract representation of a zero-numerosity category
Highlights d Neurons in monkey PFC and VIP were recorded before and after numerosity training d P... more Highlights d Neurons in monkey PFC and VIP were recorded before and after numerosity training d PFC showed improved responses to numerosity during active discrimination d VIP neurons continued to respond to numerosity just as before training d Flexible numerical PFC representations contrast with stable VIP coding
Prefrontal cortex (PFC) and posterior parietal cortex are important for maintaining behaviorally ... more 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-tonumerosity 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. Neuron
Flexibly applying abstract rules is a hallmark feature of executive functioning represented by pr... more 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 goaldirected behavior. Neuron Dopamine Enhances Rule Coding in PFC
Switching flexibly between behavioral goals is a hallmark of executive control and requires integ... more Switching flexibly between behavioral goals is a hallmark of executive control and requires integration of external and internal information. We recorded single-neuron correlates of different numerical representations (sensory-, working memory-, and rule-related activity) in the dorsal premotor area (PMd), the cingulate motor areas (CMA), and the ventral intraparietal sulcus (VIP) and compared them to previous recordings in the lateral prefrontal cortex (PFC). Two monkeys were trained to encode and memorize numerosities and flexibly switch between two abstract quantitative rules based on rule cues. Almost 20% of randomly selected PFC and PMd neurons significantly represented the numerical rule in a behaviorally relevant manner, approximately twice as many as in the CMA and VIP. Rule selectivity was significantly better for PMd neurons than for PFC cells. Seemingly at the expense of rule selectivity, however, sensory-and memoryrelated numerosity activity was greatly diminished compared with previous delayed match-to-numerosity studies. These findings suggest the involvement of the frontal premotor areas in strategic planning such as rule following. Moreover, the results emphasize that the coding capacities of neurons in association cortical areas are far more dynamic depending on task demands than previously thought.
The lateral prefrontal cortex (PFC), a hub of higher-level cognitive processing, is strongly modu... more 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.
The primate prefrontal cortex (PFC) plays a cardinal role in forming abstract categories and conc... more The primate prefrontal cortex (PFC) plays a cardinal role in forming abstract categories and concepts. However, it remains elusive how this is accomplished and to what extent the interaction of functionally distinct neuron classes underlies this representation. Here, we inferred the major cortical cell types, putative pyramidal cells, and interneurons by characterizing the waveforms of action potentials recorded in monkeys performing a cognitively demanding numerosity categorization task. Putative interneurons responded much faster than cells classified as pyramidal neurons and exhibited a higher reliability of category discrimination, whereas putative pyramidal cells showed a higher degree of category selectivity. An analysis of the numerosity tuning profiles and the temporal interactions of adjacent neurons indicated that inhibitory input by putative interneurons shapes the tuning to numerical categories of putative PFC pyramidal cells. These findings favor feedforward mechanisms subserving cognitive categorization and help to clarify cellular interactions in PFC microcircuits.
Processing quantity information based on abstract principles is central to intelligent behavior. ... more Processing quantity information based on abstract principles is central to intelligent behavior. Neural correlates of quantitative rule selectivity have been identified previously in the prefrontal cortex (PFC). However, whether individual neurons represent rules applied to multiple magnitude types is unknown. We recorded from PFC neurons while monkeys switched between "greater than/less than" rules applied to spatial and numerical magnitudes. A majority of rule-selective neurons responded only to the quantitative rules applied to one specific magnitude type. However, another population of neurons generalized the magnitude principle and represented the quantitative rules related to both magnitudes. This indicates that the primate brain uses rule-selective neurons specialized in guiding decisions related to a specific magnitude type only, as well as generalizing neurons that respond abstractly to the overarching concept "magnitude rules."
Proceedings of the National Academy of Sciences, 2012
Numerosity, the number of elements in a set, is a most abstract quantitative category. As such, i... more Numerosity, the number of elements in a set, is a most abstract quantitative category. As such, it is independent of the sensory modality of its elements, i.e., supramodal. Because neuronal numerosity selectivity had never been compared directly across different sensory modalities, it remained elusive if and where single neurons encode numerosity irrespective of the items’ modality. Here, monkeys were trained to discriminate both the number of auditory sounds and visual items within the same session. While the monkeys performed this task, the activity of neurons was recorded in the lateral prefrontal cortex and ventral intraparietal sulcus, structures critically involved in numerical cognition. Groups of neurons in both areas encoded either the number of auditory pulses, visual items, or both. The finding of neurons responding to numerosity irrespective of the sensory modality supports the idea of a nonverbal, supramodal neuronal code of numerical quantity in the primate brain.
Highlights d Single neurons in the human medial temporal lobe (MTL) encode numerical information ... more Highlights d Single neurons in the human medial temporal lobe (MTL) encode numerical information d Numerosity and abstract numerals are encoded by distinct neuronal populations d Numerosity representation shows a distance effect; numerals are encoded categorically d Representation of symbolic numerals may evolve from numerosity representations
The ongoing activity of prefrontal neurons after a stimulus has disappeared is considered a neuro... more The ongoing activity of prefrontal neurons after a stimulus has disappeared is considered a neuronal correlate of working memory. It depends on the delicate but poorly understood interplay between excitatory glutamatergic and inhibitory GABAergic receptor effects. We administered the NMDA receptor antagonist MK-801 and the GABA(A) receptor antagonist Bicuculline methiodide while recording cellular activity in prefrontal cortex of male rhesus monkeys performing a delayed decision task requiring working memory. The blockade of GABA(A) receptors strongly improved the selectivity of the neurons' delay activity, causing an increase in signal to noise ratio during working memory periods as well as an enhancement of the neurons' coding selectivity. The blockade of NMDA-receptors resulted in a slight enhancement of selectivity and encoding capacity of the neurons. Our findings emphasize the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.
Highlights d Stimulation of dopamine receptors enhances sensory sensitivity of PFC neurons d Stim... more Highlights d Stimulation of dopamine receptors enhances sensory sensitivity of PFC neurons d Stimulation of D1Rs and D2Rs increases signal-to-noise ratio d Neither D1R nor D2R stimulation affects the neurons' tuning sharpness d Dopamine provides a gating signal to enable access of sensory information to PFC
How is neuronal activity across distant brain regions orchestrated to allow multiple stimuli to b... more How is neuronal activity across distant brain regions orchestrated to allow multiple stimuli to be stored together in working memory, yet maintained separate for individual readout and protection from distractors? Using paired recordings in the prefrontal and parietal cortex of monkeys discriminating numbers of items (numerosities), we found that working memory content is structured by frequency-specific oscillatory synchrony. Parieto-frontal signaling in the beta band carried information about the most recent numerical input. Fronto-parietal coupling in the theta band differentiated between multiple memorized numerosities. Task-relevant and distracting stimuli were nested in spiking activity of single prefrontal neurons, but could be separated by reading out spikes at distinct phases of parietal theta oscillations. The strength of phase-locked, cross-regional memory coding predicted task performance. Frequency-specific communication channels in the fronto-parietal network could ena...
Neural oscillations in distinct frequency bands in the prefrontal cortex (pFC) are associated wit... more Neural oscillations in distinct frequency bands in the prefrontal cortex (pFC) are associated with specialized roles during cognitive control. How dopamine modulates oscillations to structure pFC functions remains unknown. We trained macaques to switch between two numerical rules and recorded local field potentials from pFC while applying dopamine receptor targeting drugs using microiontophoresis. We show that the D1 and D2 family receptors (D1Rs and D2Rs, respectively) specifically altered internally generated prefrontal oscillations, whereas sensory-evoked potentials remained unchanged. Blocking D1Rs or stimulating D2Rs increased low-frequency theta and alpha oscillations known to be involved in learning and memory. In contrast, only D1R inhibition enhanced high-frequency beta oscillations, whereas only D2R stimulation increased gamma oscillations linked to top-down and bottom-up attentional processing. These findings suggest that dopamine alters neural oscillations relevant for e...
Quantitative features of stimuli may be ordered along a magnitude continuum, or line. Magnitude r... more Quantitative features of stimuli may be ordered along a magnitude continuum, or line. Magnitude refers to parameters of different types of stimulus properties. For instance, the frequency of a sound relates to sensory and continuous stimulus properties, whereas the number of items in a set is an abstract and discrete property. In addition, within a stimulus property, magnitudes need to be processed not only in one modality, but across multiple modalities. In the sensory domain, for example, magnitude applies to both to the frequency of auditory sounds and tactile vibrations. Similarly, both the number of visual items and acoustic events constitute numerical quantity, or numerosity. To support goal-directed behavior and executive functions across time, magnitudes need to be held in working memory, the ability to briefly retain and manipulate information in mind. How different types of magnitudes across multiple modalities are represented in working memory by single neurons has only recently been explored in primates. These studies show that neurons in the frontal lobe can encode the same magnitude type across sensory modalities. However, while multimodal sensory magnitude in relative comparison tasks is represented by monotonically increasing or decreasing response functions ("summation code"), multimodal numerical quantity in absolute matching tasks is encoded by neurons tuned to preferred numerosities ("labeled-line code"). These findings indicate that most likely there is not a single type of cross-modal workingmemory code for magnitudes, but rather a flexible code that depends on the stimulus dimension as well as on the task requirements.
Neurons in the avian nidopallium caudolaterale (NCL), an endbrain structure that originated indep... more Neurons in the avian nidopallium caudolaterale (NCL), an endbrain structure that originated independently from the mammalian neocortex, process visual numerosities. To clarify the code for number in this anatomically distinct endbrain area in birds, neuronal responses to a broad range of numerosities were analyzed. We recorded single-neuron activity from the NCL of crows performing a delayed match-to-sample task with visual numerosities as discriminanda. The responses of Ͼ20% of randomly selected neurons were modulated significantly by numerosities ranging from one to 30 items. Numerosity-selective neurons showed bell-shaped tuning curves with one of the presented numerosities as preferred numerosity regardless of the physical appearance of the items. The resulting labeled-line code exhibited logarithmic compression obeying the Weber-Fechner law for magnitudes. Comparable proportions of selective neurons were found, not only during stimulus presentation, but also in the delay phase, indicating a dominant role of the NCL in numerical working memory. Both during sensory encoding and memorization of numerosities in working memory, NCL activity predicted the crows' number discrimination performance. These neuronal data reveal striking similarities across vertebrate taxa in their code for number despite convergently evolved and anatomically distinct endbrain structures.
based on largely distributed coding by single neurons that are anatomically intermingled within t... more based on largely distributed coding by single neurons that are anatomically intermingled within the same cortical area.
Working memory is associated with persistent activity in the prefrontal cortex (PFC). The neuromo... more Working memory is associated with persistent activity in the prefrontal cortex (PFC). The neuromodulator dopamine, which is released by midbrain neurons projecting into the frontal lobe, influences PFC neurons and networks via the dopamine D1 (D1R) and the D2 receptor (D2R) families. Although behavioral, clinical and computational evidence suggest an involvement of D2Rs in working memory, a neuronal explanation is missing. We report an enhancement of persistent working memory responses of PFC neurons after iontophoretically stimulating D2Rs in monkeys memorizing the number of items in a display. D2R activation improved working memory representation at the population level and increased population dynamics during the transition from visual to mnemonic representations. Computational modeling suggests that D2Rs act by modulating interneuron-to-pyramidal signaling. By increasing the population's response dynamics, D2Rs might put PFC networks in a more flexible state and enhance the neurons' working memory coding, thereby controlling dynamic cognitive control.
The prefrontal cortex (PFC) is crucial for maintaining relevant information in working memory and... more The prefrontal cortex (PFC) is crucial for maintaining relevant information in working memory and resisting interference. PFC neurons are strongly regulated by dopamine, but it is unknown whether dopamine receptors are involved in protecting target memories from distracting stimuli. We investigated the prefrontal circuit dynamics and dopaminergic modulation of targets and distractors in monkeys trained to ignore interfering stimuli in a delayed-match-to-numerosity task. We found that dopamine D1 receptors (D1Rs) modulate the recovery of task-relevant information following a distracting stimulus. The direction of modulation is cell-type-specific: in putative pyramidal neurons, D1R inhibition enhances and D1R stimulation attenuates coding of the target stimulus after the interference, while the opposite pattern is observed in putative interneurons. Our results suggest that dopaminergic neuromodulation of PFC circuits regulates mental representations of behaviourally relevant stimuli t...
Numbers that relate to the empirical property of 'rank' in a sequence (for example, 'fifth place'... more Numbers that relate to the empirical property of 'rank' in a sequence (for example, 'fifth place'). Nominal numbers Strictly linguistic labels to identify objects (for example, 'Bus number 5'). Number estimation (Also known as the analogue magnitude system and the analogue number system). A process of representing small and large set sizes that becomes systematically less precise with increasing numbers. Thus, number estimation obeys Weber's law. Subitizing (Also known as object file representation or object tracking system). The rapid tracking for up to approximately four items by assigning 'files' or 'pointers' to individual items.
Highlights d VIP neurons encode empty sets more as a distinct, nonnumerical category d In contras... more Highlights d VIP neurons encode empty sets more as a distinct, nonnumerical category d In contrast, PFC cells integrate empty sets in the numerical continuum d Prefrontal encoding of empty sets is more abstract and behaviorally relevant d Empty sets are translated into an abstract representation of a zero-numerosity category
Highlights d Neurons in monkey PFC and VIP were recorded before and after numerosity training d P... more Highlights d Neurons in monkey PFC and VIP were recorded before and after numerosity training d PFC showed improved responses to numerosity during active discrimination d VIP neurons continued to respond to numerosity just as before training d Flexible numerical PFC representations contrast with stable VIP coding
Prefrontal cortex (PFC) and posterior parietal cortex are important for maintaining behaviorally ... more 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-tonumerosity 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. Neuron
Flexibly applying abstract rules is a hallmark feature of executive functioning represented by pr... more 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 goaldirected behavior. Neuron Dopamine Enhances Rule Coding in PFC
Switching flexibly between behavioral goals is a hallmark of executive control and requires integ... more Switching flexibly between behavioral goals is a hallmark of executive control and requires integration of external and internal information. We recorded single-neuron correlates of different numerical representations (sensory-, working memory-, and rule-related activity) in the dorsal premotor area (PMd), the cingulate motor areas (CMA), and the ventral intraparietal sulcus (VIP) and compared them to previous recordings in the lateral prefrontal cortex (PFC). Two monkeys were trained to encode and memorize numerosities and flexibly switch between two abstract quantitative rules based on rule cues. Almost 20% of randomly selected PFC and PMd neurons significantly represented the numerical rule in a behaviorally relevant manner, approximately twice as many as in the CMA and VIP. Rule selectivity was significantly better for PMd neurons than for PFC cells. Seemingly at the expense of rule selectivity, however, sensory-and memoryrelated numerosity activity was greatly diminished compared with previous delayed match-to-numerosity studies. These findings suggest the involvement of the frontal premotor areas in strategic planning such as rule following. Moreover, the results emphasize that the coding capacities of neurons in association cortical areas are far more dynamic depending on task demands than previously thought.
The lateral prefrontal cortex (PFC), a hub of higher-level cognitive processing, is strongly modu... more 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.
The primate prefrontal cortex (PFC) plays a cardinal role in forming abstract categories and conc... more The primate prefrontal cortex (PFC) plays a cardinal role in forming abstract categories and concepts. However, it remains elusive how this is accomplished and to what extent the interaction of functionally distinct neuron classes underlies this representation. Here, we inferred the major cortical cell types, putative pyramidal cells, and interneurons by characterizing the waveforms of action potentials recorded in monkeys performing a cognitively demanding numerosity categorization task. Putative interneurons responded much faster than cells classified as pyramidal neurons and exhibited a higher reliability of category discrimination, whereas putative pyramidal cells showed a higher degree of category selectivity. An analysis of the numerosity tuning profiles and the temporal interactions of adjacent neurons indicated that inhibitory input by putative interneurons shapes the tuning to numerical categories of putative PFC pyramidal cells. These findings favor feedforward mechanisms subserving cognitive categorization and help to clarify cellular interactions in PFC microcircuits.
Processing quantity information based on abstract principles is central to intelligent behavior. ... more Processing quantity information based on abstract principles is central to intelligent behavior. Neural correlates of quantitative rule selectivity have been identified previously in the prefrontal cortex (PFC). However, whether individual neurons represent rules applied to multiple magnitude types is unknown. We recorded from PFC neurons while monkeys switched between "greater than/less than" rules applied to spatial and numerical magnitudes. A majority of rule-selective neurons responded only to the quantitative rules applied to one specific magnitude type. However, another population of neurons generalized the magnitude principle and represented the quantitative rules related to both magnitudes. This indicates that the primate brain uses rule-selective neurons specialized in guiding decisions related to a specific magnitude type only, as well as generalizing neurons that respond abstractly to the overarching concept "magnitude rules."
Proceedings of the National Academy of Sciences, 2012
Numerosity, the number of elements in a set, is a most abstract quantitative category. As such, i... more Numerosity, the number of elements in a set, is a most abstract quantitative category. As such, it is independent of the sensory modality of its elements, i.e., supramodal. Because neuronal numerosity selectivity had never been compared directly across different sensory modalities, it remained elusive if and where single neurons encode numerosity irrespective of the items’ modality. Here, monkeys were trained to discriminate both the number of auditory sounds and visual items within the same session. While the monkeys performed this task, the activity of neurons was recorded in the lateral prefrontal cortex and ventral intraparietal sulcus, structures critically involved in numerical cognition. Groups of neurons in both areas encoded either the number of auditory pulses, visual items, or both. The finding of neurons responding to numerosity irrespective of the sensory modality supports the idea of a nonverbal, supramodal neuronal code of numerical quantity in the primate brain.
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Papers by Andreas Nieder