Assistant Professor, Department of Biology
Ph.D. Stanford University
B.S. Stanford Univeristy
Research Interests: Function and development of neural circuits for visual processing
Overview: How do we make sense of the visual world around us? Our brain takes a pattern of photons hitting the retina and continually creates a coherent representation of what we see – detecting objects and landmarks rather than just perceiving an array of pixels. This image processing allows us to perform a range of visual tasks, such as recognizing a friend’s face, finding your way to the grocery store, and catching a frisbee. However, how these computational feats are achieved by the neural circuitry of the visual system is largely unknown. Furthermore, this circuitry is wired up by a range of cellular processes, such as arbor growth, synapse formation, and activity-dependent plasticity, and thus these developmental mechanisms effectively determine how we see the world.
Our research is focused on understanding how neural circuits perform the image processing that allows us to perform complex visual behaviors, and how these circuits are assembled during development. We use in vivo recording techniques, including high-density extracellular recording and two-photon imaging, along with molecular genetic tools to dissect neural circuits, such as cell-type specific markers, optogenetic activation and inactivation, tracing of neural pathways, and in vivo imaging of dendritic and synaptic structure. We have also implemented behavioral tasks for mice so we can perform quantitative pyschophysics to measure the animal’s perception, and we use theoretical models to understand general computational principles being instantiated by a neural circuit.
How changes in white matter might underlie improved reaction time due to practice.
Cogn Neurosci. 2016 Apr 28;:1-7
Authors: Voelker P, Piscopo D, Weible AP, Lynch G, Rothbart MK, Posner MI, Niell CM
Why does training on a task reduce the reaction time for performing it? New research points to changes in white matter pathways as one likely mechanism. These pathways connect remote brain areas involved in performing the task. Genetic variations may be involved in individual differences in the extent of this improvement. If white matter change is involved in improved reaction time with training, it may point the way toward understanding where and how generalization occurs. We examine the hypothesis that brain pathways shared by different tasks may result in improved performance of cognitive tasks remote from the training.
PMID: 27064751 [PubMed - as supplied by publisher]
Large-scale imaging of cortical dynamics during sensory perception and behavior.
J Neurophysiol. 2016 Jun 1;115(6):2852-66
Authors: Wekselblatt JB, Flister ED, Piscopo DM, Niell CM
Sensory-driven behaviors engage a cascade of cortical regions to process sensory input and generate motor output. To investigate the temporal dynamics of neural activity at this global scale, we have improved and integrated tools to perform functional imaging across large areas of cortex using a transgenic mouse expressing the genetically encoded calcium sensor GCaMP6s, together with a head-fixed visual discrimination behavior. This technique allows imaging of activity across the dorsal surface of cortex, with spatial resolution adequate to detect differential activity in local regions at least as small as 100 μm. Imaging during an orientation discrimination task reveals a progression of activity in different cortical regions associated with different phases of the task. After cortex-wide patterns of activity are determined, we demonstrate the ability to select a region that displayed conspicuous responses for two-photon microscopy and find that activity in populations of individual neurons in that region correlates with locomotion in trained mice. We expect that this paradigm will be a useful probe of information flow and network processing in brain-wide circuits involved in many sensory and cognitive processes.
PMID: 26912600 [PubMed - in process]
Reduced Cortical Activity Impairs Development and Plasticity after Neonatal Hypoxia Ischemia.
J Neurosci. 2015 Aug 26;35(34):11946-59
Authors: Ranasinghe S, Or G, Wang EY, Ievins A, McLean MA, Niell CM, Chau V, Wong PK, Glass HC, Sullivan J, McQuillen PS
UNLABELLED: Survivors of preterm birth are at high risk of pervasive cognitive and learning impairments, suggesting disrupted early brain development. The limits of viability for preterm birth encompass the third trimester of pregnancy, a "precritical period" of activity-dependent development characterized by the onset of spontaneous and evoked patterned electrical activity that drives neuronal maturation and formation of cortical circuits. Reduced background activity on electroencephalogram (EEG) is a sensitive marker of brain injury in human preterm infants that predicts poor neurodevelopmental outcome. We studied a rodent model of very early hypoxic-ischemic brain injury to investigate effects of injury on both general background and specific patterns of cortical activity measured with EEG. EEG background activity is depressed transiently after moderate hypoxia-ischemia with associated loss of spindle bursts. Depressed activity, in turn, is associated with delayed expression of glutamate receptor subunits and transporters. Cortical pyramidal neurons show reduced dendrite development and spine formation. Complementing previous observations in this model of impaired visual cortical plasticity, we find reduced somatosensory whisker barrel plasticity. Finally, EEG recordings from human premature newborns with brain injury demonstrate similar depressed background activity and loss of bursts in the spindle frequency band. Together, these findings suggest that abnormal development after early brain injury may result in part from disruption of specific forms of brain activity necessary for activity-dependent circuit development.
SIGNIFICANCE STATEMENT: Preterm birth and term birth asphyxia result in brain injury from inadequate oxygen delivery and constitute a major and growing worldwide health problem. Poor outcomes are noted in a majority of very premature (<25 weeks gestation) newborns, resulting in death or life-long morbidity with motor, sensory, learning, behavioral, and language disabilities that limit academic achievement and well-being. Limited progress has been made to develop therapies that improve neurologic outcomes. The overall objective of this study is to understand the effect of early brain injury on activity-dependent brain development and cortical plasticity to develop new treatments that will optimize repair and recovery after brain injury.
PMID: 26311776 [PubMed - indexed for MEDLINE]
Behavioral State--Getting "In The Zone".
Neuron. 2015 Jul 1;87(1):7-9
Authors: Wekselblatt JB, Niell CM
In this issue of Neuron, McGinley et al. (2015) investigate a classic observation from psychology linking arousal state with behavioral performance, demonstrating neural correlates of an "optimal" state for an auditory detection task.
PMID: 26139365 [PubMed - indexed for MEDLINE]
Cell types, circuits, and receptive fields in the mouse visual cortex.
Annu Rev Neurosci. 2015 Jul 8;38:413-31
Authors: Niell CM
Over the past decade, the mouse has emerged as an important model system for studying cortical function, owing to the advent of powerful tools that can record and manipulate neural activity in intact neural circuits. This advance has been particularly prominent in the visual cortex, where studies in the mouse have begun to bridge the gap between cortical structure and function, allowing investigators to determine the circuits that underlie specific visual computations. This review describes the advances in our understanding of the mouse visual cortex, including neural coding, the role of different cell types, and links between vision and behavior, and discusses how recent findings and new approaches can guide future studies.
PMID: 25938727 [PubMed - indexed for MEDLINE]
Layer-specific refinement of visual cortex function after eye opening in the awake mouse.
J Neurosci. 2015 Feb 25;35(8):3370-83
Authors: Hoy JL, Niell CM
The laminar structure and conserved cellular organization of mouse visual cortex provide a useful model to determine the mechanisms underlying the development of visual system function. However, the normal development of many receptive field properties has not yet been thoroughly quantified, particularly with respect to layer identity and in the absence of anesthesia. Here, we use multisite electrophysiological recording in the awake mouse across an extended period of development, starting at eye opening, to measure receptive field properties and behavioral-state modulation of responsiveness. We find selective responses for orientation, direction, and spatial frequency at eye opening, which are similar across cortical layers. After this initial similarity, we observe layer-specific maturation of orientation selectivity, direction selectivity, and linearity over the following week. Developmental increases in selectivity are most robust and similar between layers 2-4, whereas layers 5 and 6 undergo distinct refinement patterns. Finally, we studied layer-specific behavioral-state modulation of cortical activity and observed a striking reorganization in the effects of running on response gain. During week 1 after eye opening, running increases responsiveness in layers 4 and 5, whereas in adulthood, the effects of running are most pronounced in layer 2/3. Together, these data demonstrate that response selectivity is present in all layers of the primary visual cortex (V1) at eye opening in the awake mouse and identify the features of basic V1 function that are further shaped over this early developmental period in a layer-specific manner.
PMID: 25716837 [PubMed - indexed for MEDLINE]
Auditory cortex is required for fear potentiation of gap detection.
J Neurosci. 2014 Nov 12;34(46):15437-45
Authors: Weible AP, Liu C, Niell CM, Wehr M
Auditory cortex is necessary for the perceptual detection of brief gaps in noise, but is not necessary for many other auditory tasks such as frequency discrimination, prepulse inhibition of startle responses, or fear conditioning with pure tones. It remains unclear why auditory cortex should be necessary for some auditory tasks but not others. One possibility is that auditory cortex is causally involved in gap detection and other forms of temporal processing in order to associate meaning with temporally structured sounds. This predicts that auditory cortex should be necessary for associating meaning with gaps. To test this prediction, we developed a fear conditioning paradigm for mice based on gap detection. We found that pairing a 10 or 100 ms gap with an aversive stimulus caused a robust enhancement of gap detection measured 6 h later, which we refer to as fear potentiation of gap detection. Optogenetic suppression of auditory cortex during pairing abolished this fear potentiation, indicating that auditory cortex is critically involved in associating temporally structured sounds with emotionally salient events.
PMID: 25392510 [PubMed - indexed for MEDLINE]
Identification of a brainstem circuit regulating visual cortical state in parallel with locomotion.
Neuron. 2014 Jul 16;83(2):455-66
Authors: Lee AM, Hoy JL, Bonci A, Wilbrecht L, Stryker MP, Niell CM
Sensory processing is dependent upon behavioral state. In mice, locomotion is accompanied by changes in cortical state and enhanced visual responses. Although recent studies have begun to elucidate intrinsic cortical mechanisms underlying this effect, the neural circuits that initially couple locomotion to cortical processing are unknown. The mesencephalic locomotor region (MLR) has been shown to be capable of initiating running and is associated with the ascending reticular activating system. Here, we find that optogenetic stimulation of the MLR in awake, head-fixed mice can induce both locomotion and increases in the gain of cortical responses. MLR stimulation below the threshold for overt movement similarly changed cortical processing, revealing that MLR's effects on cortex are dissociable from locomotion. Likewise, stimulation of MLR projections to the basal forebrain also enhanced cortical responses, suggesting a pathway linking the MLR to cortex. These studies demonstrate that the MLR regulates cortical state in parallel with locomotion.
PMID: 25033185 [PubMed - indexed for MEDLINE]