Publications

Robert Sachdev
google scholar

• Motor cortex feedback influences sensory processing by modulating network state E Zagha, AE Casale, RNS Sachdev, MJ McGinley, DA McCormick Neuron 79 (3), 567-578
  Long-range corticocortical communication may have important roles in context-dependent sensory processing, yet we know very little about how these pathways influence their target regions. We studied the influence of primary motor cortex activity on primary somatosensory cortex in the mouse whisker system. We show that primary motor and somatosensory cortices undergo coherent, context-dependent changes in network state. Moreover, we show that motor cortex activity can drive changes in somatosensory cortex network state. A series of experiments demonstrate the involvement of the direct corticocortical feedback pathway, providing temporally precise and spatially targeted modulation of network dynamics. Cortically mediated changes in network state significantly impact sensory coding, with activated states increasing the reliability of responses to complex stimuli. By influencing network state …
• State changes rapidly modulate cortical neuronal responsiveness A Hasenstaub, RNS Sachdev, DA McCormick Journal of Neuroscience 27 (36), 9607-9622
  The responsiveness of cortical neurons is strongly and rapidly influenced by changes in the level of local network activity. In rodent somatosensory cortex, increases in network activity increase neuronal responsiveness to the intracellular injection of brief conductance stimuli but paradoxically decrease responsiveness to brief whisker deflections. However, whisker stimulation frequently evokes long-lasting changes in the level of local circuit activity. The ability of stimuli to successfully evoke prolonged increases in circuit activity is associated with both an increase in the amount of conductance evoked by a whisker stimulus and an increase in action potential responsiveness to whisker stimulation. In addition, brief whisker stimuli presented during periods of high network activity evoke postsynaptic potentials containing a greater proportion of inhibition, consistent with an increased efficiency in the activation of inhibitory …
• Effect of subthreshold up and down states on the whisker-evoked response in somatosensory cortex RNS Sachdev, FF Ebner, CJ Wilson Journal of neurophysiology 92 (6), 3511-3521
  Changes in spontaneous activity within the cortex recognized by subthreshold fluctuations of the membrane potential of cortical neurons modified the response of cortical neurons to sensory stimuli. Sensory stimuli occurring in the hyperpolarized “down” state evoked a larger depolarization and were more effective in evoking action potentials than stimuli occurring in the depolarized “up” state. Direct electrical stimulation of the thalamus showed the same dependence on the cell's state at the time of the stimulus, ruling out a strictly thalamic mechanism. Stimuli were more effective at triggering action potentials in the down state even during moderate de- or hyperpolarization of the somatic membrane potential. The postsynaptic potential (PSP) evoked from the down state was larger than the up state PSP but achieved about the same peak membrane potential, which was also near the reversal potential of the PSP …
• Journal of neurophysiology 92 (6), 3511-3521 ML Andermann, NB Gilfoy, GJ Goldey, RNS Sachdev, M Wölfel, ... Neuron 80 (4), 900-913
  Two-photon imaging of cortical neurons in vivo has provided unique insights into the structure, function, and plasticity of cortical networks, but this method does not currently allow simultaneous imaging of neurons in the superficial and deepest cortical layers. Here, we describe a simple modification that enables simultaneous, long-term imaging of all cortical layers. Using a chronically implanted glass microprism in barrel cortex, we could image the same fluorescently labeled deep-layer pyramidal neurons across their entire somatodendritic axis for several months. We could also image visually evoked and endogenous calcium activity in hundreds of cell bodies or long-range axon terminals, across all six layers in visual cortex of awake mice. Electrophysiology and calcium imaging of evoked and endogenous activity near the prism face were consistent across days and comparable with previous observations. These …
• Adaptive filtering of vibrissa input in motor cortex of rat D Kleinfeld, RNS Sachdev, LM Merchant, MR Jarvis, FF Ebner Neuron 34 (6), 1021-1034
  We studied the transformation of sensory input as it progresses from vibrissa primary sensor (S1) to motor (M1) cortex. Single-unit activity was obtained from alert adult rats that did not to whisk upon application of punctate, rhythmic stimulation of individual vibrissae. The spike response of units in S1 cortex largely reproduced the shape of the stimulus. In contrast, the spiking output of units in M1 cortex were modulated solely as a sinusoid at the repetition rate of the stimulus for frequencies between 5 and 15 Hz; this range corresponds to that of natural whisking. Thus, the S1 to M1 transformation extracts the fundamental frequency from a spectrally rich stimulus. We discuss our results in terms of a band-pass filter with a center frequency that adapts to the change in stimulation rate.
• Role of the basal forebrain cholinergic projection in somatosensory cortical plasticity RNS Sachdev, SM Lu, RG Wiley, FF Ebner Journal of neurophysiology 79 (6), 3216-3228
  Trimming all but two whiskers in adult rats produces a predictable change in cortical cell-evoked responses characterized by increased responsiveness to the two intact whiskers and decreased responsiveness to the trimmed whiskers. This type of synaptic plasticity in rat somatic sensory cortex, called “whisker pairing plasticity,” first appears in cells above and below the layer IV barrels. These are also the cortical layers that receive the densest cholinergic inputs from the nucleus basalis. The present study assesses whether the cholinergic inputs to cortex have a role in regulating whisker pairing plasticity. To do this, cholinergic basal forebrain fibers were eliminated using an immunotoxin specific for these fibers. A …
• Neocortical networks entrain neuronal circuits in cerebellar cortex H Roš, RNS Sachdev, Y Yu, N Šestan, DA McCormick Journal of Neuroscience 29 (33), 10309-10320
  Activity in neocortex is often characterized by synchronized oscillations of neurons and networks, resulting in the generation of a local field potential (LFP) and electroencephalogram. Do the neuronal networks of the cerebellum also generate synchronized oscillations and are they under the influence of those in the neocortex? Here we show that, in the absence of any overt external stimulus, the cerebellar cortex generates a slow oscillation that is correlated with that of the neocortex. Disruption of the neocortical slow oscillation abolishes the cerebellar slow oscillation, whereas blocking cerebellar activity has no overt effect on the neocortex. We provide evidence that the cerebellar slow oscillation results in part from the activation of granule, Golgi, and Purkinje neurons. In particular, we show that granule and Golgi cells discharge trains of single spikes, and Purkinje cells generate complex spikes, during the “up …
• Divergent movement of adjacent whiskers RNS Sachdev, T Sato, FF Ebner Journal of neurophysiology 87 (3), 1440-1448
  The current view of whisker movement is that ∼25 whiskers on each side of the face move in synchrony. To determine whether whiskers are constrained to move together, we trained rats to use two whiskers on the same side of the face in simple behavioral tasks and videotaped the whiskers during the task. Here we report that the movement of adjacent whiskers is usually synchronous but can diverge: 1) the distance between whiskers can vary dramatically during movement; 2) one whisker can move while the second one remains stationary; 3) two whiskers can simultaneously move in opposite directions; and4) one whisker can be maintained in contact with an object while the other is retracted and protracted. The frequency of whisker movement during the task falls within the previously reported range for rats whisking freely into air or performing roughness discrimination with their whiskers. Our data also suggest …
• Decreased subcortical cholinergic arousal in focal seizures JE Motelow, W Li, Q Zhan, AM Mishra, RNS Sachdev, G Liu, ... Neuron 85 (3), 561-572
  Impaired consciousness in temporal lobe seizures has a major negative impact on quality of life. The prevailing view holds that this disorder impairs consciousness by seizure spread to the bilateral temporal lobes. We propose instead that seizures invade subcortical regions and depress arousal, causing impairment through decreases rather than through increases in activity. Using functional magnetic resonance imaging in a rodent model, we found increased activity in regions known to depress cortical function, including lateral septum and anterior hypothalamus. Importantly, we found suppression of intralaminar thalamic and brainstem arousal systems and suppression of the cortex. At a cellular level, we found reduced firing of identified cholinergic neurons in the brainstem pedunculopontine tegmental nucleus and basal forebrain. Finally, we used enzyme-based amperometry to demonstrate reduced cholinergic …
• Improved methods for marking active neuron populations B Moeyaert, G Holt, R Madangopal, A Perez-Alvarez, BC Fearey, ... Nature communications 9 (1), 4440
  Marking functionally distinct neuronal ensembles with high spatiotemporal resolution is a key challenge in systems neuroscience. We recently introduced CaMPARI, an engineered fluorescent protein whose green-to-red photoconversion depends on simultaneous light exposure and elevated calcium, which enabled marking active neuronal populations with single-cell and subsecond resolution. However, CaMPARI (CaMPARI1) has several drawbacks, including background photoconversion in low calcium, slow kinetics and reduced fluorescence after chemical fixation. In this work, we develop CaMPARI2, an improved sensor with brighter green and red fluorescence, faster calcium unbinding kinetics and decreased photoconversion in low calcium conditions. We demonstrate the improved performance of CaMPARI2 in mammalian neurons and in vivo in larval zebrafish brain and mouse visual cortex. Additionally …
• Unilateral vibrissa contact: changes in amplitude but not timing of rhythmic whisking RNS Sachdev, RW Berg, G Champney, D Kleinfeld, FF Ebner Somatosensory & motor research 20 (2), 163-169
  Electromyographic recordings from the mystacial pad of rats were used to assess the effect of unilateral vibrissa contact on the bilateral movement of the vibrissae. A first group of animals was trained to whisk freely in air and served to establish the baseline variability in bilateral symmetry. We observed that the electromyogram (EMG) activity across the two mystacial pads was rhythmic and synchronous to within 2 ms on a whisk-by-whisk basis; this value is small in comparison with the ˜50 ms required for protraction during the whisk cycle. A second group of animals was trained to use their vibrissae to contact a sensor that was located on one side of the head. The average EMG activity across the two pads was synchronous at the time of vibrissa contact, albeit with higher variability than for the case of free whisking. In contrast, the average amplitude of the activity on the contact vs noncontact side of the face was …
• Respiration drives network activity and modulates synaptic and circuit processing of lateral inhibition in the olfactory bulb ME Phillips, RNS Sachdev, DC Willhite, GM Shepherd Journal of Neuroscience 32 (1), 85-98
  Respiration produces rhythmic activity in the entire olfactory system, driving neurons in the olfactory epithelium, olfactory bulb (OB), and cortex. The rhythmic nature of this activity is believed to be a critical component of sensory processing. OB projection neurons, mitral and tufted cells exhibit both spiking and subthreshold membrane potential oscillations rhythmically coupled to respiration. However, the network and synaptic mechanisms that produce respiration-coupled activity, and the effects of respiration on lateral inhibition, a major component of sensory processing in OB circuits, are not known. Is respiration-coupled activity in mitral and tufted cells produced by sensory synaptic inputs from nasal airflow alone, cortico-bulbar feedback, or intrinsic membrane properties of the projection neurons? Does respiration facilitate or modulate the activity of inhibitory lateral circuits in the OB? Here, in vivo intracellular …