Robert Sachdev - Academia.edu (original) (raw)
Papers by Robert Sachdev
bioRxiv, 2021
Neocortical layer (L) 1 is a locus for interactions between long-range inputs, L1 interneurons an... more Neocortical layer (L) 1 is a locus for interactions between long-range inputs, L1 interneurons and apical tuft dendrites of pyramidal neurons. Even though we have a wealth of information about L1, the level and effect of local input to this layer have not been quantified. Here we characterized the input to L1 of mouse somatosensory cortex with fast blue, monosynaptic rabies and optogenetics. Our work shows that most of the input to L1 is local, and that both local and long-range inputs to this layer arise predominantly from L2/3 and L5 neurons. Subtypes of L5 and L6b neurons project to the overlying L1 with different probabilities. VIP and SST interneurons in L2/3 and L5 also innervate L1. A subset of local L5, the intratelencephalic, pyramidal neurons, drive L1 interneurons but have no effect on L5 apical tuft dendrites. Monosynaptic rabies-based retrograde labelling reveals presynaptic boutons covering the entire somato-dendritic axis of pyramidal neurons, including in L1. When fa...
Raw and some derived datasets supplementary to: Dominiak SE, Nashaat MA, Sehara K, Oraby H, Larku... more Raw and some derived datasets supplementary to: Dominiak SE, Nashaat MA, Sehara K, Oraby H, Larkum ME, Sachdev RNS (2019) Whisking asymmetry signals motor preparation and the behavioral state of mice. J Neurosci, in press.
You might find this additional info useful... This article cites 54 articles, 21 of which you can... more You might find this additional info useful... This article cites 54 articles, 21 of which you can access for free at:
Current Biology, 2021
SUMMARY Prompt execution of planned motor action is essential for survival. The interactions betw... more SUMMARY Prompt execution of planned motor action is essential for survival. The interactions between frontal cortical circuits and the basal ganglia are central to goal-oriented action selection and initiation.1–4 In rodents, the ventromedial thalamic nucleus (VM) is one of the critical nodes that conveys the output of the basal ganglia to the frontal cortical areas including the anterior lateral motor cortex (ALM).5–9 Recent studies showed the critical role of ALM and its interplay with the motor thalamus in preparing sensory-cued rewarded movements, specifically licking.10–12 Work in primates suggests that the basal ganglia output to the motor thalamus transmits an urgency or vigor signal,13–15 which leads to shortened reaction times and faster movement initiation. As yet, little is known about what signals are transmitted from the motor thalamus to the cortex during cued movements and how these signals contribute to movement initiation. In the present study, we employed a tactile-cued licking task in mice while monitoring reaction times of the initial lick. We found that inactivation of ALM delayed the initiation of cued licking. Two-photon Ca2+ imaging of VM axons revealed that the majority of the axon terminals in ALM were transiently active during licking. Their activity was predictive of the time of the first lick. Chemogenetic and optogenetic manipulation of VM axons in ALM indicated that VM inputs facilitate the initiation of cue-triggered and impulsive licking in trained mice. Our results suggest that VM thalamocortical inputs increase the probability and vigor of initiating planned motor responses.
The lipid phosphatase Pten (phosphatase and tensin homologue on chromosome 10) is a key tumour su... more The lipid phosphatase Pten (phosphatase and tensin homologue on chromosome 10) is a key tumour suppressor gene and an important regulator of neuronal signalling. Pten mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intellectual disability, and epilepsy. Pten enzymatic activity is regulated by a cluster of phosphorylation sites at the C-terminus of the protein. Here we specifically focussed on the role of Pten T366 phosphorylation and generated a knock-in mouse line in which Pten T366 was substituted with alanine (PtenT366A/T366A). We identify that phosphorylation of Pten at T366 controls neuron size and connectivity of brain circuits involved in sensory processing. We show in behavioural tests that PtenT366/T366A mice exhibit cognitive deficits and selective sensory impairments, with significant differences in male individuals. We identify restricted cellul...
Navigation through complex environments requires motor planning, motor preparation and the coordi... more Navigation through complex environments requires motor planning, motor preparation and the coordination between multiple sensory–motor modalities. For example, the stepping motion when we walk is coordinated with motion of the torso, arms, head and eyes. In rodents, movement of the animal through the environment is often coordinated with whisking. Here we trained head fixed mice – navigating a floating Airtrack plus maze – to overcome their directional preference and use cues indicating the direction of movement expected in each trial. Once cued, mice had to move backward out of a lane, then turn in the correct direction, and enter a new lane. In this simple paradigm, as mice begin to move backward, they position their whiskers asymmetrically: whiskers on one side of the face protract, and on the other side they retract. This asymmetry reflected the turn direction. Additionally, on each trial, mice move their eyes conjugately in the direction of the upcoming turn. Not only do they m...
Frontiers in Systems Neuroscience, 2020
A central function of the brain is to plan, predict and imagine the effect of movement in a dynam... more A central function of the brain is to plan, predict and imagine the effect of movement in a dynamically changing environment. Here we show that in mice head fixed in a plus-maze, floating on air, and trained to pick lanes based on visual stimuli, the asymmetric movement and position of whiskers on the two sides of the face signals whether the animal is moving, turning, expecting reward or licking. We show that 1) we can decode and predict the behavioral state of the animal based on this asymmetry, 2) that tactile input from whiskers indicates little about the behavioral state, and 3) that movement of the nose correlates with asymmetry, indicating that facial expression of the mouse is itself correlated with behavioral state. Amazingly, the movement of whiskers – a behavior that is not instructed or necessary in the task--informs an observer about what a mouse is doing in the maze. Thus, these mobile tactile sensors reflect a behavioral and movement-preparation state of the mouse.
Journal of Neurophysiology, 2000
Whisker deflection typically evokes a transient volley of action potentials in rat somatic sensor... more Whisker deflection typically evokes a transient volley of action potentials in rat somatic sensory (SI) barrel cortex. Postexcitatory inhibition is thought to quickly terminate the cortical cell response to whisker deflection. Using dual electrode extracellular recording in awake rats, we describe an infrequent type of cell response in which stimulation of single hairs consistently blocks the ongoing discharge of neurons without prior excitation (I-only inhibition). Reconstruction of the recording sites indicates that I-only inhibition occurs most frequently when the recording site is clearly in the septum or at the barrel-septum junction. The same cells that respond with I-only inhibition to one whisker can show an excitatory discharge to other whiskers, usually followed by inhibition. Stimulation of either nose hairs or the large mystacial vibrissa can evoke I-only inhibition in SI cortex. I-only inhibition is most commonly observed at low stimulus frequencies (∼1 Hz). At stimulus...
Nature Communications, 2018
Journal of Neurophysiology, 2000
Trimming all whiskers except two on one side of an adult rat's face results in cortical plast... more Trimming all whiskers except two on one side of an adult rat's face results in cortical plasticity in which the spared whiskers, D2 and one D-row surround whisker (either D1 or D3), evoked responses containing more spikes than the response evoked by the cut whisker (called whisker pairing plasticity). Previously we have reported that acetylcholine (ACh) depletion in cortex prevents surround D-row whisker plasticity from developing within the barrel cortex. In this study we examined whether the animal's active use of its two intact whiskers can restore some aspects of plasticity in the ACh-depleted cortex. To achieve this goal, ACh was depleted from barrel field cortex, and 14 days after the depletion surgery, whiskers were trimmed and animals were trained on a whisker-dependent gap crossing task. After 7 days of training, animals were anesthetized with urethan and prepared for single-unit recording. Training the ACh-depleted, whisker-paired animals resulted in a significant ...
Seminars in Neuroscience, 1997
Journal of neurophysiology, 2016
Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent o... more Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent on sensory feedback that constantly adjusts behavior. To investigate the underlying neuronal correlates of natural behavior, it is useful to have access to state-of-the-art recording equipment (e.g., 2-photon imaging, patch recordings, etc.) that frequently requires head fixation. This limitation has been addressed with various approaches such as virtual reality/air ball or treadmill systems. However, achieving multimodal realistic behavior in these systems can be challenging. These systems are often also complex and expensive to implement. Here we present "Air-Track," an easy-to-build head-fixed behavioral environment that requires only minimal computational processing. The Air-Track is a lightweight physical maze floating on an air table that has all the properties of the "real" world, including multiple sensory modalities tightly coupled to motor actions. To test th...
The Journal of physiology, 2017
The genetically encoded fluorescent calcium integrator calcium-modulated photoactivatable ratiobe... more The genetically encoded fluorescent calcium integrator calcium-modulated photoactivatable ratiobetric integrator (CaMPARI) reports calcium influx induced by synaptic and neural activity. Its fluorescence is converted from green to red in the presence of violet light and calcium. The rate of conversion - the sensitivity to activity - is tunable and depends on the intensity of violet light. Synaptic activity and action potentials can independently initiate significant CaMPARI conversion. The level of conversion by subthreshold synaptic inputs is correlated to the strength of input, enabling optical readout of relative synaptic strength. When combined with optogenetic activation of defined presynaptic neurons, CaMPARI provides an all-optical method to map synaptic connectivity. The calcium-modulated photoactivatable ratiometric integrator (CaMPARI) is a genetically encoded calcium integrator that facilitates the study of neural circuits by permanently marking cells active during user-s...
eNeuro
Here, we describe an automated optical method for tracking animal behavior in both head-fixed and... more Here, we describe an automated optical method for tracking animal behavior in both head-fixed and freely moving animals, in real time and offline. It takes advantage of an off-the-shelf camera system, the Pixy camera, designed as a fast vision sensor for robotics that uses a color-based filtering algorithm at 50 Hz to track objects. Using customized software, we demonstrate the versatility of our approach by first tracking the rostro-caudal motion of individual adjacent row (D1, D2) or arc whiskers (β, γ), or a single whisker and points on the whisker pad, in head-fixed mice performing a tactile task. Next, we acquired high-speed video and Pixy data simultaneously and applied the pixy-based real-time tracking to high-speed video data. With this approach, we expand the temporal resolution of the Pixy camera and track motion (post hoc) at the limit of high-speed video frame rates. Finally, we show that this system is flexible: it can be used to track individual whisker or limb positio...
Journal of Neurophysiology, 2015
A widely accepted view is that wakefulness is a state in which the entire cortical mantle is pers... more A widely accepted view is that wakefulness is a state in which the entire cortical mantle is persistently activated, and therefore desynchronized. Consequently, the EEG is dominated by low-amplitude, high-frequency fluctuations. This view is currently under revision because the 1–4 Hz delta rhythm is often evident during “quiet” wakefulness in rodents and nonhuman primates. Here we used intracranial EEG recordings to assess the occurrence of delta rhythm in 18 awake human beings. Our recordings reveal rhythmic delta during wakefulness at 10% of all recording sites. Delta rhythm could be observed in a single cortical lobe or in multiple lobes. Sites with high delta could flip between high and low delta power or could be in a persistently high delta state. Finally, these sites were rarely identified as the sites of seizure onset. Thus rhythmic delta can dominate the background operation and activity of some neocortical circuits in awake human beings.
bioRxiv, 2021
Neocortical layer (L) 1 is a locus for interactions between long-range inputs, L1 interneurons an... more Neocortical layer (L) 1 is a locus for interactions between long-range inputs, L1 interneurons and apical tuft dendrites of pyramidal neurons. Even though we have a wealth of information about L1, the level and effect of local input to this layer have not been quantified. Here we characterized the input to L1 of mouse somatosensory cortex with fast blue, monosynaptic rabies and optogenetics. Our work shows that most of the input to L1 is local, and that both local and long-range inputs to this layer arise predominantly from L2/3 and L5 neurons. Subtypes of L5 and L6b neurons project to the overlying L1 with different probabilities. VIP and SST interneurons in L2/3 and L5 also innervate L1. A subset of local L5, the intratelencephalic, pyramidal neurons, drive L1 interneurons but have no effect on L5 apical tuft dendrites. Monosynaptic rabies-based retrograde labelling reveals presynaptic boutons covering the entire somato-dendritic axis of pyramidal neurons, including in L1. When fa...
Raw and some derived datasets supplementary to: Dominiak SE, Nashaat MA, Sehara K, Oraby H, Larku... more Raw and some derived datasets supplementary to: Dominiak SE, Nashaat MA, Sehara K, Oraby H, Larkum ME, Sachdev RNS (2019) Whisking asymmetry signals motor preparation and the behavioral state of mice. J Neurosci, in press.
You might find this additional info useful... This article cites 54 articles, 21 of which you can... more You might find this additional info useful... This article cites 54 articles, 21 of which you can access for free at:
Current Biology, 2021
SUMMARY Prompt execution of planned motor action is essential for survival. The interactions betw... more SUMMARY Prompt execution of planned motor action is essential for survival. The interactions between frontal cortical circuits and the basal ganglia are central to goal-oriented action selection and initiation.1–4 In rodents, the ventromedial thalamic nucleus (VM) is one of the critical nodes that conveys the output of the basal ganglia to the frontal cortical areas including the anterior lateral motor cortex (ALM).5–9 Recent studies showed the critical role of ALM and its interplay with the motor thalamus in preparing sensory-cued rewarded movements, specifically licking.10–12 Work in primates suggests that the basal ganglia output to the motor thalamus transmits an urgency or vigor signal,13–15 which leads to shortened reaction times and faster movement initiation. As yet, little is known about what signals are transmitted from the motor thalamus to the cortex during cued movements and how these signals contribute to movement initiation. In the present study, we employed a tactile-cued licking task in mice while monitoring reaction times of the initial lick. We found that inactivation of ALM delayed the initiation of cued licking. Two-photon Ca2+ imaging of VM axons revealed that the majority of the axon terminals in ALM were transiently active during licking. Their activity was predictive of the time of the first lick. Chemogenetic and optogenetic manipulation of VM axons in ALM indicated that VM inputs facilitate the initiation of cue-triggered and impulsive licking in trained mice. Our results suggest that VM thalamocortical inputs increase the probability and vigor of initiating planned motor responses.
The lipid phosphatase Pten (phosphatase and tensin homologue on chromosome 10) is a key tumour su... more The lipid phosphatase Pten (phosphatase and tensin homologue on chromosome 10) is a key tumour suppressor gene and an important regulator of neuronal signalling. Pten mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intellectual disability, and epilepsy. Pten enzymatic activity is regulated by a cluster of phosphorylation sites at the C-terminus of the protein. Here we specifically focussed on the role of Pten T366 phosphorylation and generated a knock-in mouse line in which Pten T366 was substituted with alanine (PtenT366A/T366A). We identify that phosphorylation of Pten at T366 controls neuron size and connectivity of brain circuits involved in sensory processing. We show in behavioural tests that PtenT366/T366A mice exhibit cognitive deficits and selective sensory impairments, with significant differences in male individuals. We identify restricted cellul...
Navigation through complex environments requires motor planning, motor preparation and the coordi... more Navigation through complex environments requires motor planning, motor preparation and the coordination between multiple sensory–motor modalities. For example, the stepping motion when we walk is coordinated with motion of the torso, arms, head and eyes. In rodents, movement of the animal through the environment is often coordinated with whisking. Here we trained head fixed mice – navigating a floating Airtrack plus maze – to overcome their directional preference and use cues indicating the direction of movement expected in each trial. Once cued, mice had to move backward out of a lane, then turn in the correct direction, and enter a new lane. In this simple paradigm, as mice begin to move backward, they position their whiskers asymmetrically: whiskers on one side of the face protract, and on the other side they retract. This asymmetry reflected the turn direction. Additionally, on each trial, mice move their eyes conjugately in the direction of the upcoming turn. Not only do they m...
Frontiers in Systems Neuroscience, 2020
A central function of the brain is to plan, predict and imagine the effect of movement in a dynam... more A central function of the brain is to plan, predict and imagine the effect of movement in a dynamically changing environment. Here we show that in mice head fixed in a plus-maze, floating on air, and trained to pick lanes based on visual stimuli, the asymmetric movement and position of whiskers on the two sides of the face signals whether the animal is moving, turning, expecting reward or licking. We show that 1) we can decode and predict the behavioral state of the animal based on this asymmetry, 2) that tactile input from whiskers indicates little about the behavioral state, and 3) that movement of the nose correlates with asymmetry, indicating that facial expression of the mouse is itself correlated with behavioral state. Amazingly, the movement of whiskers – a behavior that is not instructed or necessary in the task--informs an observer about what a mouse is doing in the maze. Thus, these mobile tactile sensors reflect a behavioral and movement-preparation state of the mouse.
Journal of Neurophysiology, 2000
Whisker deflection typically evokes a transient volley of action potentials in rat somatic sensor... more Whisker deflection typically evokes a transient volley of action potentials in rat somatic sensory (SI) barrel cortex. Postexcitatory inhibition is thought to quickly terminate the cortical cell response to whisker deflection. Using dual electrode extracellular recording in awake rats, we describe an infrequent type of cell response in which stimulation of single hairs consistently blocks the ongoing discharge of neurons without prior excitation (I-only inhibition). Reconstruction of the recording sites indicates that I-only inhibition occurs most frequently when the recording site is clearly in the septum or at the barrel-septum junction. The same cells that respond with I-only inhibition to one whisker can show an excitatory discharge to other whiskers, usually followed by inhibition. Stimulation of either nose hairs or the large mystacial vibrissa can evoke I-only inhibition in SI cortex. I-only inhibition is most commonly observed at low stimulus frequencies (∼1 Hz). At stimulus...
Nature Communications, 2018
Journal of Neurophysiology, 2000
Trimming all whiskers except two on one side of an adult rat's face results in cortical plast... more Trimming all whiskers except two on one side of an adult rat's face results in cortical plasticity in which the spared whiskers, D2 and one D-row surround whisker (either D1 or D3), evoked responses containing more spikes than the response evoked by the cut whisker (called whisker pairing plasticity). Previously we have reported that acetylcholine (ACh) depletion in cortex prevents surround D-row whisker plasticity from developing within the barrel cortex. In this study we examined whether the animal's active use of its two intact whiskers can restore some aspects of plasticity in the ACh-depleted cortex. To achieve this goal, ACh was depleted from barrel field cortex, and 14 days after the depletion surgery, whiskers were trimmed and animals were trained on a whisker-dependent gap crossing task. After 7 days of training, animals were anesthetized with urethan and prepared for single-unit recording. Training the ACh-depleted, whisker-paired animals resulted in a significant ...
Seminars in Neuroscience, 1997
Journal of neurophysiology, 2016
Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent o... more Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent on sensory feedback that constantly adjusts behavior. To investigate the underlying neuronal correlates of natural behavior, it is useful to have access to state-of-the-art recording equipment (e.g., 2-photon imaging, patch recordings, etc.) that frequently requires head fixation. This limitation has been addressed with various approaches such as virtual reality/air ball or treadmill systems. However, achieving multimodal realistic behavior in these systems can be challenging. These systems are often also complex and expensive to implement. Here we present "Air-Track," an easy-to-build head-fixed behavioral environment that requires only minimal computational processing. The Air-Track is a lightweight physical maze floating on an air table that has all the properties of the "real" world, including multiple sensory modalities tightly coupled to motor actions. To test th...
The Journal of physiology, 2017
The genetically encoded fluorescent calcium integrator calcium-modulated photoactivatable ratiobe... more The genetically encoded fluorescent calcium integrator calcium-modulated photoactivatable ratiobetric integrator (CaMPARI) reports calcium influx induced by synaptic and neural activity. Its fluorescence is converted from green to red in the presence of violet light and calcium. The rate of conversion - the sensitivity to activity - is tunable and depends on the intensity of violet light. Synaptic activity and action potentials can independently initiate significant CaMPARI conversion. The level of conversion by subthreshold synaptic inputs is correlated to the strength of input, enabling optical readout of relative synaptic strength. When combined with optogenetic activation of defined presynaptic neurons, CaMPARI provides an all-optical method to map synaptic connectivity. The calcium-modulated photoactivatable ratiometric integrator (CaMPARI) is a genetically encoded calcium integrator that facilitates the study of neural circuits by permanently marking cells active during user-s...
eNeuro
Here, we describe an automated optical method for tracking animal behavior in both head-fixed and... more Here, we describe an automated optical method for tracking animal behavior in both head-fixed and freely moving animals, in real time and offline. It takes advantage of an off-the-shelf camera system, the Pixy camera, designed as a fast vision sensor for robotics that uses a color-based filtering algorithm at 50 Hz to track objects. Using customized software, we demonstrate the versatility of our approach by first tracking the rostro-caudal motion of individual adjacent row (D1, D2) or arc whiskers (β, γ), or a single whisker and points on the whisker pad, in head-fixed mice performing a tactile task. Next, we acquired high-speed video and Pixy data simultaneously and applied the pixy-based real-time tracking to high-speed video data. With this approach, we expand the temporal resolution of the Pixy camera and track motion (post hoc) at the limit of high-speed video frame rates. Finally, we show that this system is flexible: it can be used to track individual whisker or limb positio...
Journal of Neurophysiology, 2015
A widely accepted view is that wakefulness is a state in which the entire cortical mantle is pers... more A widely accepted view is that wakefulness is a state in which the entire cortical mantle is persistently activated, and therefore desynchronized. Consequently, the EEG is dominated by low-amplitude, high-frequency fluctuations. This view is currently under revision because the 1–4 Hz delta rhythm is often evident during “quiet” wakefulness in rodents and nonhuman primates. Here we used intracranial EEG recordings to assess the occurrence of delta rhythm in 18 awake human beings. Our recordings reveal rhythmic delta during wakefulness at 10% of all recording sites. Delta rhythm could be observed in a single cortical lobe or in multiple lobes. Sites with high delta could flip between high and low delta power or could be in a persistently high delta state. Finally, these sites were rarely identified as the sites of seizure onset. Thus rhythmic delta can dominate the background operation and activity of some neocortical circuits in awake human beings.