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 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.

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.

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 Striatum-projecting prefrontal cortex neurons support working memory maintenance

2021 ◽  
Author(s):  
Maria Chernysheva ◽  
Yaroslav Sych ◽  
Aleksejs Fomins ◽  
José Luis Alatorre Warren ◽  
Christopher Lewis ◽  
...  
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Delay Period ◽  
Projection Neurons ◽  
Receptor Blockade ◽  
Impaired Performance ◽  
Cellular Resolution ◽  
Nmda Receptor Blockade ◽  
Pathway Function ◽  
Freely Moving

ABSTRACTThe medial prefrontal cortex (mPFC) and the dorsomedial striatum (dmStr) are linked to working memory (WM) but how striatum-projecting mPFC neurons contribute to WM encoding, maintenance, or retrieval remains unclear. Here, we probed mPFC→dmStr pathway function in freely-moving mice during a T-maze alternation test of spatial WM. Fiber photometry of GCaMP6m-labeled mPFC→dmStr projection neurons revealed strongest activity during the delay period that requires WM maintenance. Demonstrating causality, optogenetic inhibition of mPFC→dmStr neurons only during the delay period impaired performance. Conversely, enhancing mPFC→dmStr pathway activity—via pharmacological suppression of HCN1 or by optogenetic activation during the delay— alleviated WM impairment induced by NMDA receptor blockade. Consistently, cellular-resolution miniscope imaging resolved preferred activation of >50% mPFC→dmStr neurons during WM maintenance. This subpopulation was distinct from neurons showing preference for encoding and retrieval. In all periods, including the delay, neuronal sequences were evident. Striatum-projecting mPFC neurons thus critically contribute to spatial WM maintenance.

Attenuation of Delay-Period Activity of Monkey Prefrontal Neurons by an α2-Adrenergic Antagonist During an Oculomotor Delayed-Response Task

1998 ◽  
Vol 80 (4) ◽  
pp. 2200-2205 ◽  
Author(s):  
T. Sawaguchi
Keyword(s):  
Working Memory ◽  
Target Location ◽  
Spatial Working Memory ◽  
Delay Period ◽  
Delayed Response ◽  
Peripheral Cues ◽  
Adrenergic Antagonist ◽  
Neuronal Processes ◽  
Response Task ◽  
Delayed Response Task

Sawaguchi, T. Attenuation of delay-period activity of monkey prefrontal neurons by an α2-adrenergic antagonist during an oculomotor delayed-response task. J. Neurophysiol. 80: 2200–2205, 1998. To examine the role of norepinephrine receptors in spatial working memory processes mediated by the prefrontal cortex (PFC), noradrenergic antagonists (yohimbine for α2, prazosin for α1, and propranolol for β receptors) were applied iontophoretically to neurons of the dorsolateral PFC in rhesus monkeys that performed an oculomotor delayed-response (ODR) task. The ODR task was initiated when the monkeys fixated on a central spot on a computer monitor and consisted of fixation (1 s), cue (1 of 4 peripheral cues, 0.5 s), delay (fixation cue only, 4 s), and go periods. In the go period, the subject made a memory-guided saccade to the target location that was cued before the delay period. I focused on 49 neurons that showed directional delay-period activity, i.e., a sustained increase in activity during the delay period, the magnitude of which varied significantly with the memorized target location. Iontophoretic (usually 50 nA) application of yohimbine, but not prazosin or propranolol, significantly decreased the activities of most of the neurons with directional delay-period activity ( n = 41/49, 81%). Furthermore, yohimbine attenuated the sharpness of tuning, examined by a tuning index, of delay-period activity and had a greater attenuating effect on delay-period activity than on background activity. These findings suggest that the activation of α2-adrenergic receptors in the dorsolateral PFC plays a modulatory role in neuronal processes for visuospatial working memory.

Selection and Maintenance of Saccade Goals in the Human Frontal Eye Fields

2006 ◽  
Vol 95 (6) ◽  
pp. 3923-3927 ◽  
Author(s):  
Clayton E. Curtis ◽  
Mark D'Esposito
Keyword(s):  
Working Memory ◽  
Spatial Working Memory ◽  
Response Selection ◽  
Delay Period ◽  
Delayed Response ◽  
Frontal Eye Fields ◽  
Motor Processing ◽  
Visual Encoding ◽  
Prospective Coding ◽  
Response Task

In a delayed-response task, response selection marks an important transition from sensory to motor processing. Using event-related functional magnetic resonance imaging, we imaged the human brain during performance of a novel delayed-saccade task that isolated response selection from visual encoding and motor execution. The frontal eye fields (FEFs) and intraparietal sulcus (IPS) both showed robust contra-lateralized activity time-locked to response selection. Moreover, response selection affected delay-period activity differently in these regions; it persisted throughout the memory delay period following response selection in the FEF but not IPS. Our results indicate that the FEF and IPS both make important but distinct contributions to spatial working memory. The mechanism that the FEF uses to support spatial working memory is tied to the selection and prospective coding of saccade goals, whereas the role of the IPS may be more tied to retrospective coding of sensory representations.

Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex

1989 ◽  
Vol 61 (2) ◽  
pp. 331-349 ◽  
Author(s):  
S. Funahashi ◽  
C. J. Bruce ◽  
P. S. Goldman-Rakic
Keyword(s):  
Prefrontal Cortex ◽  
Visual Field ◽  
Visual Cues ◽  
Visual Space ◽  
Delay Period ◽  
Delayed Response ◽  
Oculomotor Behavior ◽  
Dorsolateral Prefrontal ◽  
Excitatory Responses ◽  
Response Task

1. An oculomotor delayed-response task was used to examine the spatial memory functions of neurons in primate prefrontal cortex. Monkeys were trained to fixate a central spot during a brief presentation (0.5 s) of a peripheral cue and throughout a subsequent delay period (1-6 s), and then, upon the extinction of the fixation target, to make a saccadic eye movement to where the cue had been presented. Cues were usually presented in one of eight different locations separated by 45 degrees. This task thus requires monkeys to direct their gaze to the location of a remembered visual cue, controls the retinal coordinates of the visual cues, controls the monkey's oculomotor behavior during the delay period, and also allows precise measurement of the timing and direction of the relevant behavioral responses. 2. Recordings were obtained from 288 neurons in the prefrontal cortex within and surrounding the principal sulcus (PS) while monkeys performed this task. An additional 31 neurons in the frontal eye fields (FEF) region within and near the anterior bank of the arcuate sulcus were also studied. 3. Of the 288 PS neurons, 170 exhibited task-related activity during at least one phase of this task and, of these, 87 showed significant excitation or inhibition of activity during the delay period relative to activity during the intertrial interval. 4. Delay period activity was classified as directional for 79% of these 87 neurons in that significant responses only occurred following cues located over a certain range of visual field directions and were weak or absent for other cue directions. The remaining 21% were omnidirectional, i.e., showed comparable delay period activity for all visual field locations tested. Directional preferences, or lack thereof, were maintained across different delay intervals (1-6 s). 5. For 50 of the 87 PS neurons, activity during the delay period was significantly elevated above the neuron's spontaneous rate for at least one cue location; for the remaining 37 neurons only inhibitory delay period activity was seen. Nearly all (92%) neurons with excitatory delay period activity were directional and few (8%) were omnidirectional. Most (62%) neurons with purely inhibitory delay period activity were directional, but a substantial minority (38%) was omnidirectional. 6. Fifteen of the neurons with excitatory directional delay period activity also had significant inhibitory delay period activity for other cue directions. These inhibitory responses were usually strongest for, or centered about, cue directions roughly opposite those optimal for excitatory responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Models of Functional Organization of the Lateral Prefrontal Cortex in Verbal Working Memory: Evidence in Favor of the Process Model

2002 ◽  
Vol 14 (7) ◽  
pp. 1054-1063 ◽  
Author(s):  
Laura H. F. Barde ◽  
Sharon L. Thompson-Schill
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Phonological Processing ◽  
Process Model ◽  
Functional Organization ◽  
Verbal Working Memory ◽  
Delay Period ◽  
Process Models ◽  
Delayed Response ◽  
Lateral Prefrontal Cortex

Research on the functional organization of the lateral prefrontal cortex (PFC) in working memory continues to be fairly equivocal between two major frameworks: organization-by-process or organization-by-material. Although there is fairly strong evidence for organization-by-process models from event-related fMRI studies, some investigators argue that the nature of the stimulus material better defines the functional organization of the lateral PFC, particularly in more ventral regions (BA 47/45/44). Specifically, the anterior region of the ventrolateral PFC (BA 47/45) is hypothesized to subserve semantic processing while the posterior region (BA 44) may subserve phonological processing. In the current event-related fMRI study, we directly compared process-related versus material-related organizational principles in a verbal working memory task. Subjects performed a modified delayed response task in which they (1) retained a list of five words or five nonwords during the delay period (“maintenance”), or (2) performed a semantic (size reordering) or phonological (alphabetical reordering) task on the word or nonword lists, respectively (“manipulation”). We did not find evidence during the delay period of our task to support claims of anterior-posterior specializations in the ventrolateral PFC for semantic versus phonological processing. Subjects did, however, display greater neuronal activity during the delay period of manipulation trials than maintenance trials in both the dorsolateral PFC and posterior ventrolateral regions. These data are more consistent with the process model of the organization of lateral PFC in verbal working memory.

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.

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