Behavioral modulations can alter the visual tuning of neurons in the mouse thalamocortical pathway.

Behavioral influences shape processing in the retina and the dorsal lateral geniculate nucleus (dLGN), although their precise effects on visual tuning remain debated. Using 2-photon functional Ca imaging, we characterize the dynamics of dLGN axon activity in the primary visual cortex of awake behaving mice, examining the effects of visual stimulation, pupil size, stillness, locomotion, and anesthesia. In awake recordings, nasal visual motion triggers pupil dilation and, occasionally, locomotion, increasing responsiveness and leading to an overrepresentation of boutons tuned to nasal motion.

Higher-order cortical and thalamic pathways shape visual processing streams in the mouse cortex.

Mammalian visual functions rely on distributed processing across interconnected cortical and subcortical regions. In higher-order visual areas (HVAs), visual features are processed in specialized streams that integrate feedforward and higher-order inputs from intracortical and thalamocortical pathways. However, the precise circuit organization responsible for HVA specialization remains unclear.

SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo.

Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested.

Studying human neural function in vivo at the cellular level: Chasing chimeras?

Despite its importance to understanding human brain (dys)function, it has remained challenging to study human neurons in vivo. Recent approaches, using transplantation of human cortical neurons into the rodent brain, offer new prospects for the study of human neural function and disease in vivo, from molecular to circuit levels.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition.

Diversity of spatiotemporal coding reveals specialized visual processing streams in the mouse cortex.

The cerebral cortex contains diverse neural representations of the visual scene, each enabling distinct visual and spatial abilities. However, the extent to which representations are distributed or segregated across cortical areas remains poorly understood. By determining the spatial and temporal responses of >30,000 layer 2/3 pyramidal neurons, we characterize the functional organization of parallel visual streams across eight areas of the mouse cortex.

Reconsidering the Border between the Visual and Posterior Parietal Cortex of Mice.

The posterior parietal cortex (PPC) contributes to multisensory and sensory-motor integration, as well as spatial navigation. Based on primate studies, the PPC is composed of several subdivisions with differing connection patterns, including areas that exhibit retinotopy. In mice the composition of the PPC is still under debate.

Vision and Locomotion Combine to Drive Path Integration Sequences in Mouse Retrosplenial Cortex.

The retrosplenial cortex (RSC) is involved in a broad range of cognitive functions, integrating rich sensory, motor, and spatial signals from multiple brain areas, including the hippocampal system. RSC neurons show hippocampus-dependent activity reminiscent of place cell sequences. Using cellular calcium imaging in a virtual reality (VR)-based locomotion task, we investigate how the integration of visual and locomotor inputs may give rise to such activity in RSC.

Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits.

How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here, we investigate human cortical neuron development, plasticity, and function using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging of the transplanted cells reveal a coordinated developmental roadmap recapitulating key milestones of human cortical neuron development.

Characterizing the nonlinear structure of shared variability in cortical neuron populations using latent variable models.

Sensory neurons often have variable responses to repeated presentations of the same stimulus, which can significantly degrade the stimulus information contained in those responses. This information can in principle be preserved if variability is shared across many neurons, but depends on the structure of the shared variability and its relationship to sensory encoding at the population level. The structure of this shared variability in neural activity can be characterized by latent variable models, although they have thus far typically been used under restrictive mathematical assumptions, such as assuming linear transformations between the latent variables and neural activity.

Distinct Mechanisms for Visual and Motor-Related Astrocyte Responses in Mouse Visual Cortex.

Astrocytes are a major cell type in the mammalian nervous system, are in close proximity to neurons, and show rich Ca activity thought to mediate cellular outputs. Astrocytes show activity linked to sensory [1, 2] and motor [3, 4] events, reflecting local neural activity and brain-wide neuromodulatory inputs. Sensory responses are highly variable [5-10], which may reflect interactions between distinct input types [6, 7, 9].

Locomotion modulates specific functional cell types in the mouse visual thalamus.

The visual system is composed of diverse cell types that encode distinct aspects of the visual scene and may form separate processing channels. Here we present further evidence for that hypothesis whereby functional cell groups in the dorsal lateral geniculate nucleus (dLGN) are differentially modulated during behavior. Using simultaneous multi-electrode recordings in dLGN and primary visual cortex (V1) of behaving mice, we characterized the impact of locomotor activity on response amplitude, variability, correlation and spatiotemporal tuning.

Hippocampus-dependent emergence of spatial sequence coding in retrosplenial cortex.

Retrosplenial cortex (RSC) is involved in visuospatial integration and spatial learning, and RSC neurons exhibit discrete, place cell-like sequential activity that resembles the population code of space in hippocampus. To investigate the origins and population dynamics of this activity, we combined longitudinal cellular calcium imaging of dysgranular RSC neurons in mice with excitotoxic hippocampal lesions. We tracked the emergence and stability of RSC spatial activity over consecutive imaging sessions.

In vivo characterization of the electrophysiological and astrocytic responses to a silicon neuroprobe implanted in the mouse neocortex.

Silicon neuroprobes hold great potential for studies of large-scale neural activity and brain computer interfaces, but data on brain response in chronic implants is limited. Here we explored with in vivo cellular imaging the response to multisite silicon probes for neural recordings. We tested a chronic implant for mice consisting of a CMOS-compatible silicon probe rigidly implanted in the cortex under a cranial imaging window.

Fully integrated silicon probes for high-density recording of neural activity.

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials.

Sparse orthogonal population representation of spatial context in the retrosplenial cortex.

Sparse orthogonal coding is a key feature of hippocampal neural activity, which is believed to increase episodic memory capacity and to assist in navigation. Some retrosplenial cortex (RSC) neurons convey distributed spatial and navigational signals, but place-field representations such as observed in the hippocampus have not been reported. Combining cellular Ca imaging in RSC of mice with a head-fixed locomotion assay, we identified a population of RSC neurons, located predominantly in superficial layers, whose ensemble activity closely resembles that of hippocampal CA1 place cells during the same task.

Anatomy and function of an excitatory network in the visual cortex.

Circuits in the cerebral cortex consist of thousands of neurons connected by millions of synapses. A precise understanding of these local networks requires relating circuit activity with the underlying network structure. For pyramidal cells in superficial mouse visual cortex (V1), a consensus is emerging that neurons with similar visual response properties excite each other, but the anatomical basis of this recurrent synaptic network is unknown.

Removable cranial windows for long-term imaging in awake mice.

Cranial window implants in head-fixed rodents are becoming a preparation of choice for stable optical access to large areas of the cortex over extended periods of time. Here we provide a highly detailed and reliable surgical protocol for a cranial window implantation procedure for chronic wide-field and cellular imaging in awake, head-fixed mice, which enables subsequent window removal and replacement in the weeks and months after the initial craniotomy. This protocol has facilitated awake, chronic imaging in adolescent and adult mice over several months from a large number of cortical brain regions; targeted virus and tracer injections from data obtained using prior awake functional mapping; and functionally targeted two-photon imaging across all cortical layers in awake mice using a microprism attachment to the cranial window.

Cortico-cortical projections in mouse visual cortex are functionally target specific.

Neurons in primary sensory cortex have diverse response properties, whereas higher cortical areas are specialized. Specific connectivity may be important for areal specialization, particularly in the mouse, where neighboring neurons are functionally diverse. To examine whether higher visual areas receive functionally specific input from primary visual cortex (V1), we used two-photon calcium imaging to measure responses of axons from V1 arborizing in three areas with distinct spatial and temporal frequency preferences.

Local diversity and fine-scale organization of receptive fields in mouse visual cortex.

Many thousands of cortical neurons are activated by any single sensory stimulus, but the organization of these populations is poorly understood. For example, are neurons in mouse visual cortex--whose preferred orientations are arranged randomly--organized with respect to other response properties? Using high-speed in vivo two-photon calcium imaging, we characterized the receptive fields of up to 100 excitatory and inhibitory neurons in a 200 μm imaged plane. Inhibitory neurons had nonlinearly summating, complex-like receptive fields and were weakly tuned for orientation.

Direct activation of sparse, distributed populations of cortical neurons by electrical microstimulation.

For over a century, electrical microstimulation has been the most direct method for causally linking brain function with behavior. Despite this long history, it is still unclear how the activity of neural populations is affected by stimulation. For example, there is still no consensus on where activated cells lie or on the extent to which neural processes such as passing axons near the electrode are also activated.

Local origin of field potentials in visual cortex.

The local field potential (LFP) is increasingly used to measure the combined activity of neurons within a region of tissue. Yet, available estimates of the size of this region are highly disparate, ranging from several hundred microns to a few millimeters. To measure the size of this region directly, we used a combination of multielectrode recordings and optical imaging.

Functional mechanisms shaping lateral geniculate responses to artificial and natural stimuli.

Functional models of the early visual system should predict responses not only to simple artificial stimuli but also to sequences of complex natural scenes. An ideal testbed for such models is the lateral geniculate nucleus (LGN). Mechanisms shaping LGN responses include the linear receptive field and two fast adaptation processes, sensitive to luminance and contrast.

The statistical computation underlying contrast gain control.

In the early visual system, a contrast gain control mechanism sets the gain of responses based on the locally prevalent contrast. The measure of contrast used by this adaptation mechanism is commonly assumed to be the standard deviation of light intensities relative to the mean (root-mean-square contrast). A number of alternatives, however, are possible.