Biology subjects

Rudebeck, P. H.

Publications and source records attributed to Rudebeck, P. H..

18 recordsLinked to original sources

bioRxiv2026

Dynamic geometry remapping of neural activity within frontal and subcortical areas during decision-making

Decision-making involves dynamic evaluation of competing options. Recording 16,495 neurons across nine frontal and subcortical areas in macaques revealed brain-wide fluctuations between encoding the attributes of available options. These dynamic representations track deliberation and scale with decision difficulty. Instead of binding attribute information of different options together, our analyses show that these representations are associated with dynamic area- and attribute-specific changes in neural geometry.

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bioRxiv2024

Consistent hierarchies of single-neuron timescales in mice, macaques and humans

The intrinsic timescales of single neurons are thought to be hierarchically organized across the cortex. This conclusion, however, is primarily based on analyses of neural responses from macaques. Whether hierarchical variation in timescales is a general brain organizing principle across mammals remains unclear. Here we took a cross-species approach and estimated neuronal timescales of thousands of single neurons recorded across multiple areas in mice, monkeys, and humans using a task-agnostic method. We identify largely consistent hierarchies of timescales in frontal and limbic regions across species: hippocampus had the shortest timescale whereas anterior cingulate cortex had the longest. Within this scheme, variability across species was found, most notably in amygdala and orbitofrontal cortex. We show that variation in timescales is not simply related to differences in spiking statistics nor the result of cytoarchitectonic features such as cortical granularity. Thus, hierarchically organized timescales are a consistent organizing principle across species and appear to be related to a combination of intrinsic and extrinsic factors. HighlightsO_LISimilar hierarchies of single neuron timescales exist across humans, macaques, and mice C_LIO_LIHumans diverge from an otherwise conserved hierarchy in amygdala and OFC C_LIO_LITimescale variability in ventral frontal cortex is not entirely related to cytoarchitecture C_LI

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bioRxiv2024

Ventrolateral prefrontal cortex in macaques guides decisions in different learning contexts

Flexibly adjusting our behavioral strategies based on the environmental context is critical to maximize rewards. Ventrolateral prefrontal cortex (vlPFC) has been implicated in both learning and decision-making for probabilistic rewards, although how context influences these processes remains unclear. We collected functional neuroimaging data while rhesus macaques performed a probabilistic learning task in two contexts: one with novel and another with familiar visual stimuli. We found that activity in vlPFC encoded rewards irrespective of the context but encoded behavioral strategies that depend on reward outcome (win-stay/lose-shift) preferentially in novel contexts. Functional connectivity between vlPFC and anterior cingulate cortex varied with behavioral strategy in novel learning blocks. By contrast, connectivity between vlPFC and mediodorsal thalamus was highest when subjects repeated a prior choice. Furthermore, pharmacological D2-receptor blockade altered behavioral strategies during learning and resting-state vlPFC activity. Taken together, our results suggest that multiple vlPFC-linked circuits contribute to adaptive decision-making in different contexts.

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bioRxiv2024

Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks

Deep brain stimulation (DBS) is an emerging therapeutic option for treatment resistant neurological and psychiatric disorders, most notably depression. Despite this, little is known about the anatomical and functional mechanisms that underlie this therapy. Here we targeted stimulation to the white matter adjacent to the subcallosal anterior cingulate cortex (SCC-DBS) in macaques, modeling the location in the brain proven effective for depression. We demonstrate that SCC-DBS has a selective effect on white matter macro- and micro-structure in the cingulum bundle distant to where stimulation was delivered. SCC-DBS also decreased functional connectivity between subcallosal and posterior cingulate cortex, two areas linked by the cingulum bundle and implicated in depression. Our data reveal that white matter remodeling as well as functional effects contribute to DBSs therapeutic efficacy.

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bioRxiv2024

Dissociable representations of decision variables within subdivisions of macaque orbitofrontal and ventrolateral frontal cortex

Ventral frontal cortex (VFC) in macaques is involved in many affective and cognitive processes and has a key role in flexibly guiding reward-based decision-making. VFC is composed of a set of anatomically distinct subdivisions that are within the orbitofrontal cortex, ventrolateral prefrontal cortex, and anterior insula. In part, because prior studies have lacked the resolution to test for differences, it is unclear if neural representations related to decision-making are dissociable across these subdivisions. Here we recorded the activity of thousands of neurons within eight anatomically defined subregions of VFC in macaque monkeys performing a two-choice probabilistic task for different fruit juices outcomes. We found substantial variation in the encoding of decision variables across these eight subdivisions. Notably, ventrolateral subdivision 12l was unique relative to the other areas that we recorded from as the activity of single neurons integrated multiple attributes when monkeys evaluated the different choice options. Activity within 12o, by contrast, more closely represented reward probability and whether reward was received on a given trial. Orbitofrontal area 11m/l contained more specific representations of the quality of the outcome that could be earned later on. We also found that reward delivery encoding was highly distributed across all VFC subregions, while the properties of the reward, such as its flavor, were more strongly represented in areas 11m/l and 13m. Taken together, our work reveals the diversity of encoding within the various anatomically distinct subdivisions of VFC in primates. SIGNIFICANCE STATEMENTVentral frontal cortex (VFC) is essential for flexible decision-making and is composed of many anatomically defined subdivisions. How neural representations related to decision-making vary or not between these subdivisions is unclear. Here we recorded single neuron activity from eight anatomically distinct subdivisions of VFC while macaques made choices between stimuli based on the probability of receiving different flavored fruit juices. We report that neural representations across these subdivisions were dissociable. Area 12l exhibiting the most integrated representations of decision variables at the level of single neurons. By contrast, activity in area 12o was closely related to reward probability whereas activity in area 11m/l and 13m represented juice flavor. Thus, neural representations are distinct across anatomically separable parts of VFC.

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bioRxiv2024

Comparing the limbic-frontal connectome across the primate order: conservation of connections and implications for translational neuroscience

The interaction of the limbic system and frontal cortex of the primate brain is important in many affective behaviors. For this reason, it is heavily implicated in a number of psychiatric conditions. This system is often studied in the macaque monkey, the most largely-used non-human primate model species. However, how evolutionary conserved this system is and how well results obtained in any model species translate to the human can only be understood by studying its organization across the primate order. Here, we present an investigation of the topology of limbic-frontal connections across seven species, representing all major branches of the primate family tree. We show that dichotomous organization of amydalofugal and uncinate connections with frontal cortex is conserved across all species. Subgenual connectivity of the cingulum bundle, however, seems less prominent in prosimian and New World monkey brains. These results inform both translational neuroscience and primate brain evolution.

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bioRxiv2023

Pharmacological modulation of dopamine D1 and D2 receptors reveals distinct neural networks related to probabilistic learning in non-human primates.

The neurotransmitter dopamine (DA) has a multifaceted role in healthy and disordered brains through its action on multiple subtypes of dopaminergic receptors. How modulation of these receptors influences learning and motivation by altering intrinsic brain-wide networks remains unclear. Here we performed parallel behavioral and resting-state functional MRI experiments after administration of two different DA receptor antagonists in macaque monkeys. Systemic administration of SCH-23390 (D1 antagonist) slowed probabilistic learning when subjects had to learn new stimulus-reward associations and diminished functional connectivity (FC) in cortico-cortical and fronto-striatal connections. By contrast, haloperidol (D2 antagonist) improved learning and broadly enhanced FC in cortical connections. Further comparisons between the effect of SCH-23390/haloperidol on behavioral and resting-state FC revealed specific cortical and subcortical networks associated with the cognitive and motivational effects of DA manipulation, respectively. Thus, we reveal distinct brain-wide networks that are associated with the dopaminergic control of learning and motivation via DA receptors. Significance StatementD1 and D2 receptors are heavily implicated in cognitive and motivational processes, as well as in a number of psychiatric disorders. Despite this, little is known about how selective manipulation of these different receptors impacts cognition through changing activity across brain-wide intrinsic networks. Here, we examined the acute behavioral and brain-wide effects of D1 and D2 receptor-selective antagonists, SCH-23390 and haloperidol, in macaques performing a probabilistic learning task. SCH administration diminished, and haloperidol improved, animals task performance. Mirroring these effects on behavior, SCH reduced, and haloperidol increased, the resting-state functional connectivity across brain-wide networks, most notably in the cortico-striatal areas. Thus, our results highlight the opposing effects of D1 and D2 receptor modulation on the brain and behavior.

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bioRxiv2023

Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice

Short abstractThe basolateral amygdala (BLA) projects to the frontal cortex (FC) in both rodents and primates, but the comparative organization of single-neuron BLA-FC projections is unknown. Using a barcoded connectomic approach, we found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens are similarly organized in mice and macaques, BLA-FC connections differ.

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bioRxiv2023

Preferences reveal separable valuation systems in prefrontal-limbic circuits

Individual preferences for the flavor of different foods and fluids exert a strong influence on behavior. Most current theories posit that preferences are integrated with other state variables in orbitofrontal cortex (OFC), which is thought to derive the relative subjective value of available options to drive choice behavior. Here we report that instead of a single integrated valuation system in OFC, another separate one is centered in ventrolateral prefrontal cortex (vlPFC) in macaque monkeys. Specifically, we found that OFC and vlPFC preferentially represent outcome flavor and outcome probability, respectively, and that preferences are separately integrated into these two aspects of subjective valuation. In addition, vlPFC, but not OFC, represented the outcome probability for the two options separately, with the difference between these representations reflecting the degree of preference. Thus, there are at least two separable valuation systems that work in concert to guide choices and that both are biased by preferences.

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bioRxiv2023

High-throughput sequencing of macaque basolateral amygdala projections reveals dissociable connectional motifs with frontal cortex

The basolateral amygdala (BLA) projects widely across the macaque frontal cortex1-4, and amygdalo-frontal projections are critical for optimal emotional responding5 and decision- making6. Yet, little is known about the single-neuron architecture of these projections: namely, whether single BLA neurons project to multiple parts of the frontal cortex. Here, we use MAPseq7 to determine the projection patterns of over 3000 macaque BLA neurons. We found that one-third of BLA neurons have two or more distinct targets in parts of frontal cortex and of subcortical structures. Further, we reveal non-random structure within these branching patterns such that neurons with four targets are more frequently observed than those with two or three, indicative of widespread networks. Consequently, these multi-target single neurons form distinct networks within medial and ventral frontal cortex consistent with their known functions in regulating mood and decision-making. Additionally, we show that branching patterns of single neurons shape functional networks in the brain as assessed by fMRI-based functional connectivity. These results provide a neuroanatomical basis for the role of the BLA in coordinating brain-wide responses to valent stimuli8 and highlight the importance of high- resolution neuroanatomical data for understanding functional networks in the brain.

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bioRxiv2021

Resting-state fMRI-based screening of deschloroclozapine in rhesus macaques predicts dosage-dependent behavioral effects

Chemogenetic techniques such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable transient, reversible, and minimally invasive manipulation of neural activity in vivo. Their development in non-human primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we utilize resting-state functional MRI (rs-fMRI), a non-invasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brain-wide resting-state functional connectivity in seven rhesus macaques without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Additional behavioral tests confirmed a negligible impact of 0.1 mg/kg DCZ on socio-emotional behaviors as well as on reaction time in a probabilistic learning task. 0.3 mg/kg DCZ did, however, slow responses in the probabilistic learning task, suggesting attentional or motivational deficits associated with hyperconnectivity in fronto-temporo-parietal networks. Our study highlights both the excellent selectivity of DCZ as a DREADD actuator, and the side-effects of its excess dosage. The results demonstrate the translational value of rs-fMRI as a drug-screening tool to accelerate the development of chemogenetics in primates.

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bioRxiv2021

Interaction between decision-making and interoceptive representations of bodily arousal in frontal cortex

Decision-making and representations of arousal are intimately linked. Behavioral investigations have classically shown that either too little or too much bodily arousal is detrimental to decision-making, indicating that there is an inverted U relationship between bodily arousal and performance. How these processes interact at the level of single neurons as well as the neural circuits involved are unclear. Here we recorded neural activity from orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaque monkeys while they made reward-guided decisions. Heart rate (HR) was also recorded and used as a proxy for bodily arousal. Recordings were made both before and after subjects received excitotoxic lesions of the bilateral amygdala. In intact monkeys, higher HR facilitated reaction times (RTs). Concurrently, a set of neurons in OFC and dACC selectively encoded trial-by-trial variations in HR independent of reward value. After amygdala lesions, HR increased and the relationship between HR and RTs was reversed. Concurrent with this change, there was an increase in the proportion of dACC neurons encoding HR. Applying a novel population-coding analysis, we show that after bilateral amygdala lesions the balance of encoding in dACC is skewed away from signaling either reward value or choice direction towards HR coding around the time that choices are made. Taken together, the present results provide insight into how bodily arousal and decision-making are signaled in frontal cortex. Significance statementHow bodily arousal states influence decision-making has been a central question in psychology, but the neural mechanisms are unclear. We recorded heart rate, a measure of bodily arousal, while simultaneously monitoring neural activity in orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaques making reward-guided decisions. In intact macaques higher HR was associated with shorter reaction times. Concurrently, the activity of a set of neurons in OFC and dACC selectively encoded HR. Following amygdala lesions, HR generally increased and now the relationship between HR and reaction times was reversed. At the neural level, the balance of encoding in dACC shifted towards signaling HR, suggesting a specific mechanism through which bodily arousal influences decision-making.

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bioRxiv2020

Inferring brain-wide interactions using data-constrained recurrent neural network models

Behavior arises from the coordinated activity of numerous anatomically and functionally distinct brain regions. Modern experimental tools allow unprecedented access to large neural populations spanning many interacting regions brain-wide. Yet, understanding such large-scale datasets necessitates both scalable computational models to extract meaningful features of inter-region communication and principled theories to interpret those features. Here, we introduce Current-Based Decomposition (CURBD), an approach for inferring brain-wide interactions using data-constrained recurrent neural network models that directly reproduce experimentally-obtained neural data. CURBD leverages the functional interactions inferred by such models to reveal directional currents between multiple brain regions. We first show that CURBD accurately isolates inter-region currents in simulated networks with known dynamics. We then apply CURBD to multi-region neural recordings obtained from mice during running, macaques during Pavlovian conditioning, and humans during memory retrieval to demonstrate the widespread applicability of CURBD to untangle brain-wide interactions underlying behavior from a variety of neural datasets.

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bioRxiv2018

Behavioral effect of chemogenetic inhibition is directly related to receptor transduction levels in rhesus monkeys

We used inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male macaque monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-N-oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hsyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD- transduced cells using stereological analysis of mCherry-immunolabeled cells. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared to monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histological analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory.\n\nSignificance StatementCognitive domains such as working memory and executive function are mediated by the dorsolateral prefrontal cortex (dlPFC). Impairments in these domains are common in neurodegenerative diseases as well as normal aging. The present study sought to measure deficits in a spatial delayed response task following activation of viral-vector transduced inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) receptors in rhesus macaques and compare this to the level of transduction in dlPFC using stereology. We found a significant relationship between the extent of DREADD transduction and the magnitude of behavioral deficit following administration of the DREADD actuator compound clozapine-N- oxide (CNO). These results demonstrate it will be critical to validate transduction to ensure DREADDs remain a powerful tool for neuronal disruption.

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bioRxiv2018

Quantitative analysis of synaptic pathology and neuroinflammation: an initial study in a female rhesus monkey model of the “synaptic” phase of Alzheimer’s disease

BackgroundSoluble oligomers of the A{beta} peptide (A{beta}Os) are toxins that target and disrupt synapses. Generation of A{beta}Os has been recently recognized as a probable initiating event in Alzheimers disease (AD), leading to cognitive impairment. There is a translational gap in AD studies, with promising drugs developed based on work in rodent models failing in AD patients in clinical trials. Additionally, although women have a two-fold greater lifetime risk of developing AD compared to men, females have not been a focus of preclinical studies. Thus, we sought to develop a model of A{beta}O toxicity in female rhesus monkeys, to take advantage of the more highly differentiated cortical structure in this species as well as the similarities in the endocrine system between rhesus monkeys and humans.\n\nMethodsRepeated intracerebroventricular (i.c.v) injections of A{beta}Os were performed in adult female rhesus monkeys. Controls were unoperated aged matched monkeys. High-resolution confocal microscopy and morphometric analysis of Alexa 568 (A568) filled neurons were used to evaluate synaptic, neuronal, and glial markers in the dorsolateral prefrontal cortex (dlPFC) and hippocampus after A{beta}O injections. Cerebrospinal fluid (CSF) and brain tissue were also collected and analyzed for biomarkers of AD pathology, including: phosphorylated Tau protein (pTau), total Tau, A{beta}1-42, A{beta}1-40 and TNF- levels.\n\nResultsHere, we report that A{beta}O injection into the lateral ventricle of the brain induces loss of 37% of thin spines in targeted dlPFC neurons, an area highly vulnerable in AD and aging. Further, A{beta}Os associate with the synaptic marker PSD95, inducing loss of more than 60% of local excitatory synapses. A{beta}Os induce a robust neuroinflammatory response in the hippocampus, far from the injection site, with numerous activated ameboid microglia and TNF- release. Finally, A{beta}Os increased CSF levels of A{beta}1-42, pTau Ser396 and pTau Ser199, but not A{beta}1-40 or total Tau.\n\nConclusionsThese initial findings from detailed quantitative analysis of effects of A{beta}O administration on synapses in a female nonhuman primate model are a very promising step toward understanding the mechanism of early AD pathogenesis in the primate brain, and may help develop an effective disease-modifying therapy of high relevance to womens health.

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bioRxiv2017

Lack of evidence for sex differences in higher cognitive function in macaques

Here we assessed whether higher cognitive function differed between male and female rhesus monkeys using tests of episodic memory and strategy implementation. We did not find any difference between males and females on behavioral performance or on analyses of grey matter volume of key regions. Our findings suggest that, at least where higher cognitive function in healthy monkeys is concerned, the sexes may not differ.

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bioRxiv2017

A Theta Band Network Involving Prefrontal Cortex Unique To Human Episodic Memory

Episodic memory, everyday memory for events, is fundamental to our lives. We tested patients undergoing intracranial electroencephalography (intracranial EEG) monitoring for the localization of medically-refractory epilepsy on a well-characterized paradigm that requires episodic memory. Here we report that an anatomically diffuse network characterized by thetaband (4-7 Hz) coherence is activated at the time of a choice that requires episodic memory. This distinct network pattern of oscillatory activity is absent in situations that do not require episodic memory. The episodic network we identified spans prefrontal and temporal lobes and coherence between these areas was greatest during memory encoding. Our data provide novel empirical evidence for a set of brain areas that supports episodic memory in humans.\n\nSignificance StatementSynchronous oscillations of electrical fields are thought to support brain processes such as language, movement, memory and learning. However, little is known about which types of synchronous oscillations are needed for which process. We performed invasive recordings of electrical activity in patients undergoing surgical management for epilepsy while they perform different types of memory tasks. We found synchronous oscillations in the theta band (4-7 Hz) correlate with performance in an episodic memory. This pattern of oscillations activates a distinct network of brain regions from a task that does not require episodic memory. This finding advances our understanding of the brain systems that support each process.

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bioRxiv2017

Amygdala Input Differentially Influences Prefrontal Local Field Potential And Single Neuron Encoding Of Reward-Based Decisions

Reward-guided behaviors require functional interaction between amygdala, orbital (OFC), and medial (MFC) divisions of prefrontal cortex, but the neural mechanisms underlying these interactions are unclear. Here, we used a decoding approach to analyze local field potentials (LFPs) recorded from OFC and MFC of monkeys engaged in a stimulus-choice task, before and after excitotoxic amygdala lesions. Whereas OFC LFP responses were strongly modulated by the amount of reward associated with each stimulus, MFC responses best represented which stimulus subjects decided to choose. This was counter to what we observed in the level of single neurons where their activity was closely associated with the value of the stimuli presented on each trial. After lesions of the amygdala, stimulus-reward value and choice encoding were reduced in OFC and MFC, respectively. However, while the lesion-induced decrease in OFC LFP encoding of stimulus-reward value mirrored changes in single neuron activity, reduced choice encoding in MFC LFPs was distinct from changes in single neuron activity. Thus, LFPs and single neurons represent different information required for decision-making in OFC and MFC. At the circuit-level, amygdala input to these two areas play a distinct role in stimulus-reward encoding in OFC and choice encoding in MFC.

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