Associate 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.
Cortical signatures of wakeful somatosensory processing.
Sci Rep. 2018 Aug 10;8(1):11977
Authors: Song C, Piscopo DM, Niell CM, Knöpfel T
Sensory inputs carry critical information for the survival of an organism. In mice, tactile information conveyed by the whiskers is of high behavioural relevance, and is broadcasted across cortical areas beyond the primary somatosensory cortex. Mesoscopic voltage sensitive dye imaging (VSDI) of cortical population response to whisker stimulations has shown that seemingly 'simple' sensory stimuli can have extended impact on cortical circuit dynamics. Here we took advantage of genetically encoded voltage indicators (GEVIs) that allow for cell type-specific monitoring of population voltage dynamics in a chronic dual-hemisphere transcranial windowed mouse preparation to directly compare the cortex-wide broadcasting of sensory information in wakening (lightly anesthetized to sedated) and awake mice. Somatosensory-evoked cortex-wide dynamics is altered across brain states, with anatomically sequential hyperpolarising activity observed in the awake cortex. GEVI imaging revealed cortical activity maps with increased specificity, high spatial coverage, and at the timescale of cortical information processing.
PMID: 30097603 [PubMed - in process]
Changes in white matter in mice resulting from low-frequency brain stimulation.
Proc Natl Acad Sci U S A. 2018 07 03;115(27):E6339-E6346
Authors: Piscopo DM, Weible AP, Rothbart MK, Posner MI, Niell CM
Recent reports have begun to elucidate mechanisms by which learning and experience produce white matter changes in the brain. We previously reported changes in white matter surrounding the anterior cingulate cortex in humans after 2-4 weeks of meditation training. We further found that low-frequency optogenetic stimulation of the anterior cingulate in mice increased time spent in the light in a light/dark box paradigm, suggesting decreased anxiety similar to what is observed following meditation training. Here, we investigated the impact of this stimulation at the cellular level. We found that laser stimulation in the range of 1-8 Hz results in changes to subcortical white matter projection fibers in the corpus callosum. Specifically, stimulation resulted in increased oligodendrocyte proliferation, accompanied by a decrease in the g-ratio within the corpus callosum underlying the anterior cingulate cortex. These results suggest that low-frequency stimulation can result in activity-dependent remodeling of myelin, giving rise to enhanced connectivity and altered behavior.
PMID: 29915074 [PubMed - indexed for MEDLINE]
Seeing with a biased visual cortical map.
J Neurophysiol. 2018 07 01;120(1):272-273
Authors: Mazade R, Niell CM, Alonso JM
PMID: 29742024 [PubMed - in process]
Refinement of Spatial Receptive Fields in the Developing Mouse Lateral Geniculate Nucleus Is Coordinated with Excitatory and Inhibitory Remodeling.
J Neurosci. 2018 May 09;38(19):4531-4542
Authors: Tschetter WW, Govindaiah G, Etherington IM, Guido W, Niell CM
Receptive field properties of individual visual neurons are dictated by the precise patterns of synaptic connections they receive, including the arrangement of inputs in visual space and features such as polarity (On vs Off). The inputs from the retina to the lateral geniculate nucleus (LGN) in the mouse undergo significant refinement during development. However, it is unknown how this refinement corresponds to the establishment of functional visual response properties. Here we conducted in vivo and in vitro recordings in the mouse LGN, beginning just after natural eye opening, to determine how receptive fields develop as excitatory and feedforward inhibitory retinal afferents refine. Experiments used both male and female subjects. For in vivo assessment of receptive fields, we performed multisite extracellular recordings in awake mice. Spatial receptive fields at eye-opening were >2 times larger than in adulthood, and decreased in size over the subsequent week. This topographic refinement was accompanied by other spatial changes, such as a decrease in spot size preference and an increase in surround suppression. Notably, the degree of specificity in terms of On/Off and sustained/transient responses appeared to be established already at eye opening and did not change. We performed in vitro recordings of the synaptic responses evoked by optic tract stimulation across the same time period. These recordings revealed a pairing of decreased excitatory and increased feedforward inhibitory convergence, providing a potential mechanism to explain the spatial receptive field refinement.SIGNIFICANCE STATEMENT The development of precise patterns of retinogeniculate connectivity has been a powerful model system for understanding the mechanisms underlying the activity-dependent refinement of sensory systems. Here we link the maturation of spatial receptive field properties in the lateral geniculate nucleus (LGN) to the remodeling of retinal and inhibitory feedforward convergence onto LGN neurons. These findings should thus provide a starting point for testing the cell type-specific plasticity mechanisms that lead to refinement of different excitatory and inhibitory inputs, and for determining the effect of these mechanisms on the establishment of mature receptive fields in the LGN.
PMID: 29661964 [PubMed - in process]
TU-Tagging: A Method for Identifying Layer-Enriched Neuronal Genes in Developing Mouse Visual Cortex.
eNeuro. 2017 Sep-Oct;4(5):
Authors: Tomorsky J, DeBlander L, Kentros CG, Doe CQ, Niell CM
Thiouracil (TU)-tagging is an intersectional method for covalently labeling newly transcribed RNAs within specific cell types. Cell type specificity is generated through targeted transgenic expression of the enzyme uracil phosphoribosyl transferase (UPRT); temporal specificity is generated through a pulse of the modified uracil analog 4TU. This technique has been applied in mouse using a Cre-dependent UPRT transgene, CA>GFPstop>HA-UPRT, to profile RNAs in endothelial cells, but it remained untested whether 4TU can cross the blood-brain barrier (BBB) or whether this transgene can be used to purify neuronal RNAs. Here, we crossed the CA>GFPstop>HA-UPRT transgenic mouse to a Sepw1-cre line to express UPRT in layer 2/3 of visual cortex or to an Nr5a1-cre line to express UPRT in layer 4 of visual cortex. We purified thiol-tagged mRNA from both genotypes at postnatal day (P)12, as well as from wild-type (WT) mice not expressing UPRT (background control). We found that a comparison of Sepw1-purified RNA to WT or Nr5a1-purified RNA allowed us to identify genes enriched in layer 2/3 of visual cortex. Here, we show that Cre-dependent UPRT expression can be used to purify cell type-specific mRNA from the intact mouse brain and provide the first evidence that 4TU can cross the BBB to label RNA in vivo.
PMID: 29085897 [PubMed - indexed for MEDLINE]
Rhythmic brain stimulation reduces anxiety-related behavior in a mouse model based on meditation training.
Proc Natl Acad Sci U S A. 2017 03 07;114(10):2532-2537
Authors: Weible AP, Piscopo DM, Rothbart MK, Posner MI, Niell CM
Meditation training induces changes at both the behavioral and neural levels. A month of meditation training can reduce self-reported anxiety and other dimensions of negative affect. It also can change white matter as measured by diffusion tensor imaging and increase resting-state midline frontal theta activity. The current study tests the hypothesis that imposing rhythms in the mouse anterior cingulate cortex (ACC), by using optogenetics to induce oscillations in activity, can produce behavioral changes. Mice were randomly assigned to groups and were given twenty 30-min sessions of light pulses delivered at 1, 8, or 40 Hz over 4 wk or were assigned to a no-laser control condition. Before and after the month all mice were administered a battery of behavioral tests. In the light/dark box, mice receiving cortical stimulation had more light-side entries, spent more time in the light, and made more vertical rears than mice receiving rhythmic cortical suppression or no manipulation. These effects on light/dark box exploratory behaviors are associated with reduced anxiety and were most pronounced following stimulation at 1 and 8 Hz. No effects were seen related to basic motor behavior or exploration during tests of novel object and location recognition. These data support a relationship between lower-frequency oscillations in the mouse ACC and the expression of anxiety-related behaviors, potentially analogous to effects seen with human practitioners of some forms of meditation.
PMID: 28223484 [PubMed - indexed for MEDLINE]
Long-Term Optical Access to an Estimated One Million Neurons in the Live Mouse Cortex.
Cell Rep. 2016 12 20;17(12):3385-3394
Authors: Kim TH, Zhang Y, Lecoq J, Jung JC, Li J, Zeng H, Niell CM, Schnitzer MJ
A major technological goal in neuroscience is to enable the interrogation of individual cells across the live brain. By creating a curved glass replacement to the dorsal cranium and surgical methods for its installation, we developed a chronic mouse preparation providing optical access to an estimated 800,000-1,100,000 individual neurons across the dorsal surface of neocortex. Post-surgical histological studies revealed comparable glial activation as in control mice. In behaving mice expressing a Ca2+ indicator in cortical pyramidal neurons, we performed Ca2+ imaging across neocortex using an epi-fluorescence macroscope and estimated that 25,000-50,000 individual neurons were accessible per mouse across multiple focal planes. Two-photon microscopy revealed dendritic morphologies throughout neocortex, allowed time-lapse imaging of individual cells, and yielded estimates of >1 million accessible neurons per mouse by serial tiling. This approach supports a variety of optical techniques and enables studies of cells across >30 neocortical areas in behaving mice.
PMID: 28009304 [PubMed - indexed for MEDLINE]
Vision Drives Accurate Approach Behavior during Prey Capture in Laboratory Mice.
Curr Biol. 2016 11 21;26(22):3046-3052
Authors: Hoy JL, Yavorska I, Wehr M, Niell CM
The ability to genetically identify and manipulate neural circuits in the mouse is rapidly advancing our understanding of visual processing in the mammalian brain [1, 2]. However, studies investigating the circuitry that underlies complex ethologically relevant visual behaviors in the mouse have been primarily restricted to fear responses [3-5]. Here, we show that a laboratory strain of mouse (Mus musculus, C57BL/6J) robustly pursues, captures, and consumes live insect prey and that vision is necessary for mice to perform the accurate orienting and approach behaviors leading to capture. Specifically, we differentially perturbed visual or auditory input in mice and determined that visual input is required for accurate approach, allowing maintenance of bearing to within 11° of the target on average during pursuit. While mice were able to capture prey without vision, the accuracy of their approaches and capture rate dramatically declined. To better explore the contribution of vision to this behavior, we developed a simple assay that isolated visual cues and simplified analysis of the visually guided approach. Together, our results demonstrate that laboratory mice are capable of exhibiting dynamic and accurate visually guided approach behaviors and provide a means to estimate the visual features that drive behavior within an ethological context.
PMID: 27773567 [PubMed - indexed for MEDLINE]