scholarly journals Parallel processing of working memory and temporal information by distinct types of cortical projection neurons

2021 ◽  
Author(s):  
Jung Won Bae ◽  
Huijeong Jeong ◽  
Chanmee Bae ◽  
Hyeonsu Lee ◽  
Se-Bum Paik ◽  
...  
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Temporal Information ◽  
Projection Neurons ◽  
Delayed Response ◽  
Behavioral Performance ◽  
Subcortical Structures ◽  
Cortical Projection ◽  
Different Types ◽  
Response Task

AbstractIt is unclear how different types of cortical projection neurons work together to support diverse cortical functions. We examined the discharge characteristics and inactivation effects of intratelencephalic (IT) and pyramidal tract (PT) neurons—two major types of cortical excitatory neurons that project to cortical and subcortical structures, respectively—in the medial prefrontal cortex of mice performing a delayed response task. We found that IT neurons, but not PT neurons, convey significant working memory-related signals. We also found that the inactivation of IT neurons, but not PT neurons, impairs behavioral performance. In contrast, PT neurons convey far more temporal information than IT neurons during the delay period. Our results indicate a division of labor between IT and PT projection neurons in the prefrontal cortex for the maintenance of working memory and for tracking the passage of time, respectively.

scholarly journals Parallel processing of working memory and temporal information by distinct types of cortical projection neurons

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jung Won Bae ◽  
Huijeong Jeong ◽  
Young Ju Yoon ◽  
Chan Mee Bae ◽  
Hyeonsu Lee ◽  
...  
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Delay Period ◽  
Temporal Information ◽  
Projection Neurons ◽  
Delayed Response ◽  
Subcortical Structures ◽  
Cortical Projection ◽  
Different Types ◽  
Response Task

AbstractIt is unclear how different types of cortical projection neurons work together to support diverse cortical functions. We examined the discharge characteristics and inactivation effects of intratelencephalic (IT) and pyramidal tract (PT) neurons—two major types of cortical excitatory neurons that project to cortical and subcortical structures, respectively—in the deep layer of the medial prefrontal cortex in mice performing a delayed response task. We found stronger target-dependent firing of IT than PT neurons during the delay period. We also found the inactivation of IT neurons, but not PT neurons, impairs behavioral performance. In contrast, PT neurons carry more temporal information than IT neurons during the delay period. Our results indicate a division of labor between IT and PT projection neurons in the prefrontal cortex for the maintenance of working memory and for tracking the passage of time, respectively.

scholarly journals Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys

2019 ◽  
Author(s):  
Nicholas A. Upright ◽  
Mark G. Baxter
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Rhesus Monkeys ◽  
Memory Performance ◽  
Memory Function ◽  
Muscarinic Acetylcholine Receptor ◽  
Designer Drugs ◽  
Delayed Response ◽  
Response Task ◽  
Delayed Response Task

AbstractThe most common chemogenetic neuromodulatory system, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is no longer sensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug. We investigated working memory performance after injections of three DREADD agonists, clozapine, olanzapine, and deschloroclozapine, in male rhesus monkeys tested in a spatial delayed response task. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from mean performance after vehicle in any of the four subjects. Administration of 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after administration of 0.1 mg/kg olanzapine and two monkeys were impaired after the 0.3 mg/kg dose of deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs to confirm that effects following DREADD receptor transduction are not due to the actuator drug itself, as well as validating the behavioral pharmacology of DREADD actuator drugs in the specific tasks under study.Significance StatementChemogenetic technologies, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), allow for precise and remote manipulation of neuronal circuits. In the present study, we tested monkeys in a spatial delayed response task after injections of three actuator drugs – clozapine, olanzapine, and deschloroclozapine. We found that monkeys showed significant working memory impairments after 0.2 mg/kg clozapine, 0.1 mg/kg olanzapine, and 0.3 mg/kg deschloroclozapine compared to vehicle performance. In monkeys that showed impairments, these deficits were particularly apparent at longer delay periods. It is imperative to validate the drugs and dosages in the particular behavioral test to ensure any behavior after DREADD transduction can be attributed to activation of the receptors and not administration of the actuator drug itself.

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

2018 ◽  
Author(s):  
Nicholas A. Upright ◽  
Stephen W. Brookshire ◽  
Wendy Schnebelen ◽  
Christienne G. Damatac ◽  
Patrick R. Hof ◽  
...  
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Rhesus Monkeys ◽  
Dorsolateral Prefrontal Cortex ◽  
Behavioral Effect ◽  
Designer Drug ◽  
Delayed Response ◽  
Dorsolateral Prefrontal ◽  
Response Task ◽  
Delayed Response Task

AbstractWe 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.Significance 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.

Prefrontal Cortical Representation of Visuospatial Working Memory in Monkeys Examined by Local Inactivation With Muscimol

2001 ◽  
Vol 86 (4) ◽  
pp. 2041-2053 ◽  
Author(s):  
Toshiyuki Sawaguchi ◽  
Michiyo Iba
Keyword(s):  
Working Memory ◽  
Functional Organization ◽  
Visual Fields ◽  
Local Injection ◽  
Delayed Response ◽  
Visually Guided ◽  
Visuospatial Working Memory ◽  
Prefrontal Cortical ◽  
Response Task ◽  
Spatial Locations

In primates, dorsolateral areas of the prefrontal cortex (PFC) play a major role in visuospatial working memory. To examine the functional organization of the PFC for representing visuospatial working memory, we produced reversible local inactivation, with the local injection of muscimol (5 μg, 1 μl), at various sites ( n = 100) in the dorsolateral PFC of monkeys and observed the behavioral consequences in an oculomotor delayed-response task that required memory-guided saccades for locations throughout both visual fields. At 82 sites, the local injection of muscimol induced deficits in memory-guided saccades to a few specific, usually contralateral, target locations that varied with the location of the injection site. Such deficits depended on the delay length, and longer delays were associated with larger deficits in memory-guided saccades. The injection sites and affected spatial locations of the target showed a gross topographical relationship. No deficits appeared for a control task in which the subject was required to make a visually guided saccade to a visible target. These findings suggest that a specific site in the dorsolateral PFC is responsible for the working memory process for a specific visuospatial coordinate to guide goal-directed behavior. Further, memoranda for specific visuospatial coordinates appear to be represented in a topographical memory mapwithin the dorsolateral PFC to represent visuospatial working memory processes.

scholarly journals Prefrontal and Parietal Attractor Networks Mediate Working Memory Judgments

2020 ◽  
Author(s):  
Sihai Li ◽  
Christos Constantinidis ◽  
Xue-Lian Qi
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Critical Role ◽  
Memory Task ◽  
Delayed Response ◽  
Persistent Activity ◽  
Neural Basis ◽  
Brain Areas ◽  
Dorsolateral Prefrontal

ABSTRACTThe dorsolateral prefrontal cortex plays a critical role in spatial working memory and its activity predicts behavioral responses in delayed response tasks. Here we addressed whether this predictive ability extends to categorical judgments based on information retained in working memory, and is present in other brain areas. We trained monkeys in a novel, Match-Stay, Nonmatch-Go task, which required them to observe two stimuli presented in sequence with an intervening delay period between them. If the two stimuli were different, the monkeys had to saccade to the location of the second stimulus; if they were the same, they held fixation. Neurophysiological recordings were performed in areas 8a and 46 of the dlPFC and 7a and lateral intraparietal cortex (LIP) of the PPC. We hypothesized that random drifts causing the peak activity of the network to move away from the first stimulus location and towards the location of the second stimulus would result in categorical errors. Indeed, for both areas, when the first stimulus appeared in a neuron’s preferred location, the neuron showed significantly higher firing rates in correct than in error trials. When the first stimulus appeared at a nonpreferred location and the second stimulus at a preferred, activity in error trials was higher than in correct. The results indicate that the activity of both dlPFC and PPC neurons is predictive of categorical judgments of information maintained in working memory, and the magnitude of neuronal firing rate deviations is revealing of the contents of working memory as it determines performance.SIGNIFICANCE STATEMENTThe neural basis of working memory and the areas mediating this function is a topic of controversy. Persistent activity in the prefrontal cortex has traditionally been thought to be the neural correlate of working memory, however recent studies have proposed alternative mechanisms and brain areas. Here we show that persistent activity in both the dorsolateral prefrontal cortex and posterior parietal cortex predicts behavior in a working memory task that requires a categorical judgement. Our results offer support to the idea that a network of neurons in both areas act as an attractor network that maintains information in working memory, which informs behavior.

Spatial working memory assessment by a visual-manual delayed response task: a controlled study in schizophrenia

1999 ◽  
Vol 275 (1) ◽  
pp. 9-12 ◽  
Author(s):  
P Stratta ◽  
E Daneluzzo ◽  
P Prosperini ◽  
M Bustini ◽  
M.G Marinangeli ◽  
...  
Keyword(s):  
Working Memory ◽  
Spatial Working Memory ◽  
Controlled Study ◽  
Delayed Response ◽  
Memory Assessment ◽  
Response Task ◽  
Delayed Response Task

scholarly journals Stable population coding for working memory coexists with heterogeneous neural dynamics in prefrontal cortex

2016 ◽  
Vol 114 (2) ◽  
pp. 394-399 ◽  
Author(s):  
John D. Murray ◽  
Alberto Bernacchia ◽  
Nicholas A. Roy ◽  
Christos Constantinidis ◽  
Ranulfo Romo ◽  
...  
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Neural Circuit ◽  
Temporal Dynamics ◽  
Population Level ◽  
Population Coding ◽  
Neural Dynamics ◽  
Stable Population ◽  
Neuron Activity ◽  
Delayed Response

Working memory (WM) is a cognitive function for temporary maintenance and manipulation of information, which requires conversion of stimulus-driven signals into internal representations that are maintained across seconds-long mnemonic delays. Within primate prefrontal cortex (PFC), a critical node of the brain’s WM network, neurons show stimulus-selective persistent activity during WM, but many of them exhibit strong temporal dynamics and heterogeneity, raising the questions of whether, and how, neuronal populations in PFC maintain stable mnemonic representations of stimuli during WM. Here we show that despite complex and heterogeneous temporal dynamics in single-neuron activity, PFC activity is endowed with a population-level coding of the mnemonic stimulus that is stable and robust throughout WM maintenance. We applied population-level analyses to hundreds of recorded single neurons from lateral PFC of monkeys performing two seminal tasks that demand parametric WM: oculomotor delayed response and vibrotactile delayed discrimination. We found that the high-dimensional state space of PFC population activity contains a low-dimensional subspace in which stimulus representations are stable across time during the cue and delay epochs, enabling robust and generalizable decoding compared with time-optimized subspaces. To explore potential mechanisms, we applied these same population-level analyses to theoretical neural circuit models of WM activity. Three previously proposed models failed to capture the key population-level features observed empirically. We propose network connectivity properties, implemented in a linear network model, which can underlie these features. This work uncovers stable population-level WM representations in PFC, despite strong temporal neural dynamics, thereby providing insights into neural circuit mechanisms supporting WM.

scholarly journals Making Working Memory Work: A Computational Model of Learning in the Prefrontal Cortex and Basal Ganglia

2006 ◽  
Vol 18 (2) ◽  
pp. 283-328 ◽  
Author(s):  
Randall C. O'Reilly ◽  
Michael J. Frank
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Basal Ganglia ◽  
Computational Model ◽  
Computational Models ◽  
Memory Task ◽  
Learning Mechanisms ◽  
Subcortical Structures ◽  
Credit Assignment ◽  
Gating Mechanism

The prefrontal cortex has long been thought to subserve both working memory (the holding of information online for processing) and executive functions (deciding how to manipulate working memory and perform processing). Although many computational models of working memory have been developed, the mechanistic basis of executive function remains elusive, often amounting to a homunculus. This article presents an attempt to deconstruct this homunculus through powerful learning mechanisms that allow a computational model of the prefrontal cortex to control both itself and other brain areas in a strategic, task-appropriate manner. These learning mechanisms are based on subcortical structures in the midbrain, basal ganglia, and amygdala, which together form an actor-critic architecture. The critic system learns which prefrontal representations are task relevant and trains the actor, which in turn provides a dynamic gating mechanism for controlling working memory updating. Computationally, the learning mechanism is designed to simultaneously solve the temporal and structural credit assignment problems. The model's performance compares favorably with standard backpropagation-based temporal learning mechanisms on the challenging 1-2-AX working memory task and other benchmark working memory tasks.

Prefrontal Task-Related Activity Representing Visual Cue Location or Saccade Direction in Spatial Working Memory Tasks

2002 ◽  
Vol 87 (1) ◽  
pp. 567-588 ◽  
Author(s):  
Kazuyoshi Takeda ◽  
Shintaro Funahashi
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Spatial Working Memory ◽  
Delay Period ◽  
Neuron Activity ◽  
Delayed Response ◽  
Related Activity ◽  
Visual Cue ◽  
Response Period ◽  
Dorsolateral Prefrontal

To examine what kind of information task-related activity encodes during spatial working memory processes, we analyzed single-neuron activity in the prefrontal cortex while two monkeys performed two different oculomotor delayed-response (ODR) tasks. In the standard ODR task, monkeys were required to make a saccade to the cue location after a 3-s delay, whereas in the rotatory ODR (R-ODR) task, they were required to make a saccade 90° clockwise from the cue location after the 3-s delay. By comparing the same task-related activities in these two tasks, we could determine whether such activities encoded the location of the visual cue or the direction of the saccade. One hundred twenty one neurons exhibited task-related activity in relation to at least one task event in both tasks. Among them, 41 neurons exhibited directional cue-period activity, most of which encoded the location of the visual cue. Among 56 neurons with directional delay-period activity, 86% encoded the location of the visual cue, whereas 13% encoded the direction of the saccade. Among 57 neurons with directional response-period activity, 58% encoded the direction of the saccade, whereas 35% encoded the location of the visual cue. Most neurons whose response-period activity encoded the location of the visual cue also exhibited directional delay-period activity that encoded the location of the visual cue as well. The best directions of these two activities were identical, and most of these response-period activities were postsaccadic. Therefore this postsaccadic activity can be considered a signal to terminate unnecessary delay-period activity. Population histograms encoding the location of the visual cue showed tonic sustained activation during the delay period. However, population histograms encoding the direction of the saccade showed a gradual increase in activation during the delay period. These results indicate that the transformation from visual input to motor output occurs in the dorsolateral prefrontal cortex. The analysis using population histograms suggests that this transformation occurs gradually during the delay period.

Temporally Irregular Mnemonic Persistent Activity in Prefrontal Neurons of Monkeys During a Delayed Response Task

2003 ◽  
Vol 90 (5) ◽  
pp. 3441-3454 ◽  
Author(s):  
Albert Compte, ◽  
Christos Constantinidis ◽  
Jesper Tegnér ◽  
Sridhar Raghavachari ◽  
Matthew V. Chafee ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Power Spectrum ◽  
Spike Train ◽  
Temporal Structure ◽  
Spike Trains ◽  
Delay Period ◽  
Delayed Response ◽  
Persistent Activity ◽  
Response Task ◽  
Delayed Response Task

An important question in neuroscience is whether and how temporal patterns and fluctuations in neuronal spike trains contribute to information processing in the cortex. We have addressed this issue in the memory-related circuits of the prefrontal cortex by analyzing spike trains from a database of 229 neurons recorded in the dorsolateral prefrontal cortex of 4 macaque monkeys during the performance of an oculomotor delayed-response task. For each task epoch, we have estimated their power spectrum together with interspike interval histograms and autocorrelograms. We find that 1) the properties of most (about 60%) neurons approximated the characteristics of a Poisson process. For about 25% of cells, with characteristics typical of interneurons, the power spectrum showed a trough at low frequencies (<20 Hz) and the autocorrelogram a dip near zero time lag. About 15% of neurons had a peak at <20 Hz in the power spectrum, associated with the burstiness of the spike train; 2) a small but significant task dependency of spike-train temporal structure: delay responses to preferred locations were characterized not only by elevated firing, but also by suppressed power at low (<20 Hz) frequencies; and 3) the variability of interspike intervals is typically higher during the mnemonic delay period than during the fixation period, regardless of the remembered cue. The high irregularity of neural persistent activity during the delay period is likely to be a characteristic signature of recurrent prefrontal network dynamics underlying working memory.

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