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    University - Academic staff Department: Adult Neurosurgery Position: Sr Res Scientist-Basic Life

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  • Mail Code: 5327

All Publications

  • Control of pupil responses Encyclopedia of the Human Brain Joshi, S. Elsevier. 2024; Second: 374-387

    View details for DOI 10.1016/B978-0-12-820480-1.00077-2

  • The impact of age and Alzheimer’s disease on locus coeruleus mediated neuromodulation of neural circuits and goal-directed behavior. Joshi, S. PsyArXiv. 2023

    Abstract

    Neuromodulators affect cognition and behavior via their actions on brain wide neural networks. The locus coeruleus norepinephrine (LC-NE) system is one of the brain’s major neuromodulatory systems. Aging and neurological diseases lead to changes in brain structure that impact the normal functioning of brain networks and neuromodulatory systems. Although the precise nature of this impact, its diagnosis and quantification remain a challenge, recent studies in humans and in animal models have started to reveal details about the effects of intrinsic neuromodulators on neural networks and behavior. These recent findings are beginning to suggest how systems neuroscience approaches might help develop new tests to supplement the wide range of established clinical assays for testing cognitive deficits due to aging and Alzheimer’s disease. Here, I will review what we know about networks that perform computations driving perception and action and how these networks are affected by activation of the LC-NE system. I will examine what is known about aging and Alzheimer’s disease related changes in these networks and in the LC-NE system and the resulting impact on perception and action. I will discuss the relationships between activation of this system and changes in pupil size, recently explored with precision in humans and in animal models. I will examine how, when combined with perceptual or cognitive tests, these findings provide a basis for exploring the use of pupillometry as a non-invasive assay of age- and disease-related decline in neuromodulatory function.

  • Context-dependent relationships between locus coeruleus firing patterns and coordinated neural activity in the anterior cingulate cortex. eLife Joshi, S., Gold, J. I. 2022; 11

    Abstract

    Ascending neuromodulatory projections from the locus coeruleus (LC) affect cortical neural networks via the release of norepinephrine (NE). However, the exact nature of these neuromodulatory effects on neural activity patterns in vivo is not well understood. Here, we show that in awake monkeys, LC activation is associated with changes in coordinated activity patterns in the anterior cingulate cortex (ACC). These relationships, which are largely independent of changes in firing rates of individual ACC neurons, depend on the type of LC activation: ACC pairwise correlations tend to be reduced when ongoing (baseline) LC activity increases but enhanced when external events evoke transient LC responses. Both relationships covary with pupil changes that reflect LC activation and arousal. These results suggest that modulations of information processing that reflect changes in coordinated activity patterns in cortical networks can result partly from ongoing, context-dependent, arousal-related changes in activation of the LC-NE system.

    View details for DOI 10.7554/eLife.63490

    View details for PubMedID 34994344

    View details for PubMedCentralID PMC8765756

  • Pupillometry: Arousal State or State of Mind? Current biology : CB Joshi, S. 2021; 31 (1): R32-R34

    Abstract

    Norepinephrine and acetylcholine regulate brain activity during changes in arousal and attention that are also reflected in fluctuations of the pupil. New research suggests that during goal-directed behavior, serotonin is also associated with pupil dilation.

    View details for DOI 10.1016/j.cub.2020.11.001

    View details for PubMedID 33434486

  • Pupil Size as a Window on Neural Substrates of Cognition. Trends in cognitive sciences Joshi, S., Gold, J. I. 2020; 24 (6): 466-480

    Abstract

    Cognitively driven pupil modulations reflect certain underlying brain functions. What do these reflections tell us? Here, we review findings that have identified key roles for three neural systems: cortical modulation of the pretectal olivary nucleus (PON), which controls the pupillary light reflex; the superior colliculus (SC), which mediates orienting responses, including pupil changes to salient stimuli; and the locus coeruleus (LC)-norepinephrine (NE) neuromodulatory system, which mediates relationships between pupil-linked arousal and cognition. We discuss how these findings can inform the interpretation of pupil measurements in terms of activation of these neural systems. We also highlight caveats, open questions, and key directions for future experiments for improving these interpretations in terms of the underlying neural dynamics throughout the brain.

    View details for DOI 10.1016/j.tics.2020.03.005

    View details for PubMedID 32331857

    View details for PubMedCentralID PMC7271902

  • Relationships between Pupil Diameter and Neuronal Activity in the Locus Coeruleus, Colliculi, and Cingulate Cortex. Neuron Joshi, S., Li, Y., Kalwani, R. M., Gold, J. I. 2016; 89 (1): 221-34

    Abstract

    Changes in pupil diameter that reflect effort and other cognitive factors are often interpreted in terms of the activity of norepinephrine-containing neurons in the brainstem nucleus locus coeruleus (LC), but there is little direct evidence for such a relationship. Here, we show that LC activation reliably anticipates changes in pupil diameter that either fluctuate naturally or are driven by external events during near fixation, as in many psychophysical tasks. This relationship occurs on as fine a temporal and spatial scale as single spikes from single units. However, this relationship is not specific to the LC. Similar relationships, albeit with delayed timing and different reliabilities across sites, are evident in the inferior and superior colliculus and anterior and posterior cingulate cortex. Because these regions are interconnected with the LC, the results suggest that non-luminance-mediated changes in pupil diameter might reflect LC-mediated coordination of neuronal activity throughout some parts of the brain.

    View details for DOI 10.1016/j.neuron.2015.11.028

    View details for PubMedID 26711118

    View details for PubMedCentralID PMC4707070

  • Phasic activation of individual neurons in the locus ceruleus/subceruleus complex of monkeys reflects rewarded decisions to go but not stop. The Journal of neuroscience : the official journal of the Society for Neuroscience Kalwani, R. M., Joshi, S., Gold, J. I. 2014; 34 (41): 13656-69

    Abstract

    Neurons in the brainstem nucleus locus ceruleus (LC) often exhibit phasic activation in the context of simple sensory-motor tasks. The functional role of this activation, which leads to the release of norepinephrine throughout the brain, is not yet understood in part because the conditions under which it occurs remain in question. Early studies focused on the relationship of LC phasic activation to salient sensory events, whereas more recent work has emphasized its timing relative to goal-directed behavioral responses, possibly representing the end of a sensory-motor decision process. To better understand the relationship between LC phasic activation and sensory, motor, and decision processing, we recorded spiking activity of neurons in the LC+ (LC and the adjacent, norepinephrine-containing subceruleus nucleus) of monkeys performing a countermanding task. The task required the monkeys to occasionally withhold planned, saccadic eye movements to a visual target. We found that many well isolated LC+ units responded to both the onset of the visual cue instructing the monkey to initiate the saccade and again after saccade onset, even when it was initiated erroneously in the presence of a stop signal. Many of these neurons did not respond to saccades made outside of the task context. In contrast, neither the appearance of the stop signal nor the successful withholding of the saccade elicited an LC+ response. Therefore, LC+ phasic activation encodes sensory and motor events related to decisions to execute, but not withhold, movements, implying a functional role in goal-directed actions, but not necessarily more covert forms of processing.

    View details for DOI 10.1523/JNEUROSCI.2566-14.2014

    View details for PubMedID 25297093

    View details for PubMedCentralID PMC4188964

  • Functional characterization of the extraclassical receptive field in macaque V1: contrast, orientation, and temporal dynamics. The Journal of neuroscience : the official journal of the Society for Neuroscience Henry, C. A., Joshi, S., Xing, D., Shapley, R. M., Hawken, M. J. 2013; 33 (14): 6230-42

    Abstract

    Neurons in primary visual cortex, V1, very often have extraclassical receptive fields (eCRFs). The eCRF is defined as the region of visual space where stimuli cannot elicit a spiking response but can modulate the response of a stimulus in the classical receptive field (CRF). We investigated the dependence of the eCRF on stimulus contrast and orientation in macaque V1 cells for which the laminar location was determined. The eCRF was more sensitive to contrast than the CRF across the whole population of V1 cells with the greatest contrast differential in layer 2/3. We confirmed that many V1 cells experience stronger suppression for collinear than orthogonal stimuli in the eCRF. Laminar analysis revealed that the predominant bias for collinear suppression was found in layers 2/3 and 4b. The laminar pattern of contrast and orientation dependence suggests that eCRF suppression may derive from different neural circuits in different layers, and may be comprised of two distinct components: orientation-tuned and untuned suppression. On average tuned suppression was delayed by ∼25 ms compared with the onset of untuned suppression. Therefore, response modulation by the eCRF develops dynamically and rapidly in time.

    View details for DOI 10.1523/JNEUROSCI.4155-12.2013

    View details for PubMedID 23554504

    View details for PubMedCentralID PMC3675885

  • Shedding new light on the role of the basal ganglia-superior colliculus pathway in eye movements. Current opinion in neurobiology Shires, J., Joshi, S., Basso, M. A. 2010; 20 (6): 717-25

    Abstract

    A large body of work spanning 25+ years provides compelling evidence for the involvement of the basal ganglia-superior colliculus pathway in the initiation of rapid, orienting movements of the eyes, called saccades. The role of this pathway in saccade control is similar to the role of the basal ganglia-thalamic pathway in the control of skeletal movement: a transient cessation in tonic inhibition supplied by the basal ganglia to motor structures releases movements via the direct pathway whereas a transient increase in inhibition by the basal ganglia to motor structures prevents movements via the indirect pathway. In parallel with recent advances in the study and treatment of patients with basal ganglia disease and in animal experiments in the skeletal motor system, the results of studies exploring the role of the basal ganglia-superior colliculus pathway in saccades highlight the need for a revisiting of our understanding of the role of this pathway in saccades. The discovery of many different response profiles of neurons in the substantia nigra pars reticulata of the basal ganglia and in the superior colliculus, coupled with advances in experimental and statistical techniques including sophisticated behavioral procedures and multiple neuron recording and analysis, point toward a role for the basal ganglia-superior colliculus pathway in cognitive events intervening between vision and action, such as memory, target selection and saccade choice and valuation.

    View details for DOI 10.1016/j.conb.2010.08.008

    View details for PubMedID 20829033

    View details for PubMedCentralID PMC3008502

  • Loose-patch-juxtacellular recording in vivo--a method for functional characterization and labeling of neurons in macaque V1. Journal of neuroscience methods Joshi, S., Hawken, M. J. 2006; 156 (1-2): 37-49

    Abstract

    We describe a method that uses a modified version of juxtacellular labeling [Pinault D. A novel single-cell staining procedure performed in vivo under electrophysiological control: morpho-functional features of juxtacellularly labeled thalamic cells and other central neurons with biocytin or neurobiotin. J Neurosci Meth 1996;65:113-36], which allows us to functionally characterize and subsequently label single neurons in vivo in macaque V1. The method is generally applicable in acute in vivo preparations. Extracellular recording is made with a patch electrode when the electrode is attached to the cell membrane. Initially a 'blind' search method is used as a guide to obtaining a cell attached configuration that we refer to as a loose-patch (LP). The neuron's receptive field properties are functionally characterized, the neuron is labeled and then characterization is confirmed, all in the LP configuration. There are a number of advantages of the method that we describe over other methods. First, we have found that we can obtain stable extracellular recordings for periods of hours that enable us to make a relatively comprehensive visual functional characterization of a neuron's receptive field properties. Second, because the electrode is closely apposed to the cell we obtain excellent isolation of the extracellular spike. Third, the method provides labeling that gives complete dendritic and axonal filling that survives over a number of days, which is an important feature in acute primate experiments. Fourth, the in vivo method of labeling and reconstructing neurons gives complete three-dimensional structure of the neuron including its intra-cortical axonal arbor. These features overcome known limits of the established methods of studying neuronal morphology including the Golgi stain (limited when adult tissue is used) and in vitro whole cell methods (incomplete axonal filling due to limited slice thickness). They also overcome the known limits of the established method of combined function-morphology studies i.e. intracellular recording in vivo. The modified juxtacellular method provides a reliable alternative to the difficult method of characterization by extracellular recording and subsequent intracellular labeling [Anderson JC, Martin KAC, Whitteridge D. Form, function and intracortical projections of neurons in the striate cortex of the monkey Macacus nemestrinus. Cerebral Cortex 1993;3:412-20]. We show the method can be used to record at a range of depths through V1 cortex allowing for sampling of neurons in the different layers and functional subpopulations. Links can then be made with existing knowledge about the anatomical organization of V1, the various morphological classes of neurons found therein, their functional connectivity and visual response properties.

    View details for DOI 10.1016/j.jneumeth.2006.02.004

    View details for PubMedID 16540174