Gabriel Kreiman

Widespread transcription at neuronal activity-regulated enhancers

We used genome-wide sequencing methods to study stimulus-dependent enhancer function in mouse cortical neurons. We identified ∼12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis.

Invariant visual representation by single neurons in the human brain

It takes a fraction of a second to recognize a person or an object even when seen under strikingly different conditions. How such a robust, high-level representation is achieved by neurons in the human brain is still unclear. In monkeys, neurons in the upper stages of the ventral visual pathway respond to complex images such as faces and objects and show some degree of invariance to metric properties such as the stimulus size, position and viewing angle. We have previously shown that neurons in the human medial temporal lobe (MTL) fire selectively to images of faces, animals, objects or scenes. Here we report on a remarkable subset of MTL neurons that are selectively activated by strikingly different pictures of given individuals, landmarks or objects and in some cases even by letter strings with their names. These results suggest an invariant, sparse and explicit code, which might be important in the transformation of complex visual percepts into long-term and more abstract memories.

Neural correlates of consciousness in humans

The directness and vivid quality of conscious experience belies the complexity of the underlying neural mechanisms, which remain incompletely understood. Recent work has focused on identifying the brain structures and patterns of neural activity within the primate visual system that are correlated with the content of visual consciousness. Functional neuroimaging in humans and electrophysiology in awake mokeys indicate that there are important differences between striate and extrastriate visual cortex in how well neural activity correlates with consciousness. Moreover, recent neuroimaging studies indicate that, in addition to these ventral areas of visual cortex, dorsal prefrontal and parietal areas might contribute to conscious visual experience.

Category-specific visual responses of single neurons in the human medial temporal lobe

The hippocampus, amygdala and entorhinal cortex receive convergent input from temporal neocortical regions specialized for processing complex visual stimuli and are important in the representation and recognition of visual images. Recording from 427 single neurons in the human hippocampus, entorhinal cortex and amygdala, we found a remarkable degree of category-specific firing of individual neurons on a trial-by-trial basis. Of the recorded neurons, 14% responded selectively to visual stimuli from different categories, including faces, natural scenes and houses, famous people and animals. Based on the firing rate of individual neurons, stimulus category could be predicted with a mean probability of error of 0.24. In the hippocampus, the proportion of neurons responding to spatial layouts was greater than to other categories. Our data provide direct support for the role of human medial temporal regions in the representation of different categories of visual stimuli.

Timing, Timing, Timing: Fast Decoding of Object Information from Intracranial Field Potentials in Human Visual Cortex

The difficulty of visual recognition stems from the need to achieve high selectivity while maintaining robustness to object transformations within hundreds of milliseconds. Theories of visual recognition differ in whether the neuronal circuits invoke recurrent feedback connections or not. The timing of neurophysiological responses in visual cortex plays a key role in distinguishing between bottom-up and top-down theories. Here, we quantified at millisecond resolution the amount of visual information conveyed by intracranial field potentials from 912 electrodes in 11 human subjects. We could decode object category information from human visual cortex in single trials as early as 100 ms poststimulus. Decoding performance was robust to depth rotation and scale changes. The results suggest that physiological activity in the temporal lobe can account for key properties of visual recognition. The fast decoding in single trials is compatible with feedforward theories and provides strong constraints for computational models of human vision.

Imagery neurons in the human brain

Vivid visual images can be voluntarily generated in our minds in the absence of simultaneous visual input. While trying to count the number of flowers in Van Goghs Sunflowers, understanding a description or recalling a path, subjects report forming an image in their “minds eye”. Whether this process is accomplished by the same neuronal mechanisms as visual perception has long been a matter of debate. Evidence from functional imaging, psychophysics, neurological studies and monkey electrophysiology suggests a common process, yet there are patients with deficits in one but not the other. Here we directly investigated the neuronal substrates of visual recall by recording from single neurons in the human medial temporal lobe while the subjects were asked to imagine previously viewed images. We found single neurons in the hippocampus, amygdala, entorhinal cortex and parahippocampal gyrus that selectively altered their firing rates depending on the stimulus the subjects were imagining. Of the neurons that fired selectively during both vision and imagery, the majority (88%) had identical selectivity. Our study reveals single neuron correlates of volitional visual imagery in humans and suggests a common substrate for the processing of incoming visual information and visual recall.

Object selectivity of local field potentials and spikes in the macaque inferior temporal cortex.

Local field potentials (LFPs) arise largely from dendritic activity over large brain regions and thus provide a measure of the input to and local processing within an area. We characterized LFPs and their relationship to spikes (multi and single unit) in monkey inferior temporal cortex (IT). LFP responses in IT to complex objects showed strong selectivity at 44% of the sites and tolerance to retinal position and size. The LFP preferences were poorly predicted by the spike preferences at the same site but were better explained by averaging spikes within approximately 3 mm. A comparison of separate sites suggests that selectivity is similar on a scale of approximately 800 microm for spikes and approximately 5 mm for LFPs. These observations imply that inputs to IT neurons convey selectivity for complex shapes and that such input may have an underlying organization spanning several millimeters.

Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex

Two key models for examining activity-dependent development of primary visual cortex (V1) involve either reduction of activity in both eyes via dark-rearing (DR) or imbalance of activity between the two eyes via monocular deprivation (MD). Combining DNA microarray analysis with computational approaches, RT-PCR, immunohistochemistry and physiological imaging, we find that DR leads to (i) upregulation of genes subserving synaptic transmission and electrical activity, consistent with a coordinated response of cortical neurons to reduction of visual drive, and (ii) downregulation of parvalbumin expression, implicating parvalbumin-expressing interneurons as underlying the delay in cortical maturation after DR. MD partially activates homeostatic mechanisms but differentially upregulates molecular pathways related to growth factors and neuronal degeneration, consistent with reorganization of connections after MD. Expression of a binding protein of insulin-like growth factor-1 (IGF1) is highly upregulated after MD, and exogenous application of IGF1 prevents the physiological effects of MD on ocular dominance plasticity examined in vivo.

Single-neuron correlates of subjective vision in the human medial temporal lobe

Visual information from the environment is transformed into perceptual sensations through several stages of neuronal processing. Flash suppression constitutes a striking example in which the same retinal input can give rise to two different conscious visual percepts. We directly recorded the responses of individual neurons during flash suppression in the human amygdala, entorhinal cortex, hippocampus, and parahippocampal gyrus, allowing us to explore the neuronal responses in untrained subjects at a high spatial and temporal resolution in the medial temporal lobe. Subjects were patients with pharmacologically intractable epilepsy implanted with depth electrodes to localize the seizure onset focus. We observed that the activity of two thirds of all visually selective neurons followed the perceptual alternations rather than the retinal input. None of the selective neurons responded to a perceptually suppressed stimulus. Therefore, the activity of most individual neurons in the medial temporal lobe of naive human subjects directly correlates with the phenomenal visual experience.

A quantitative theory of immediate visual recognition.

Human and non-human primates excel at visual recognition tasks. The primate visual system exhibits a strong degree of selectivity while at the same time being robust to changes in the input image. We have developed a quantitative theory to account for the computations performed by the feedforward path in the ventral stream of the primate visual cortex. Here we review recent predictions by a model instantiating the theory about physiological observations in higher visual areas. We also show that the model can perform recognition tasks on datasets of complex natural images at a level comparable to psychophysical measurements on human observers during rapid categorization tasks. In sum, the evidence suggests that the theory may provide a framework to explain the first 100-150 ms of visual object recognition. The model also constitutes a vivid example of how computational models can interact with experimental observations in order to advance our understanding of a complex phenomenon. We conclude by suggesting a number of open questions, predictions, and specific experiments for visual physiology and psychophysics.