Corticocortical feedback increases the spatial extent of normalization

Normalization has been proposed as a canonical computation operating across different brain regions, sensory modalities, and species. It provides a good phenomenological description of non-linear response properties in primary visual cortex (V1), including the contrast response function and surround suppression. Despite its widespread application throughout the visual system, the underlying neural mechanisms remain largely unknown. We recently observed that corticocortical feedback contributes to surround suppression in V1, raising the possibility that feedback acts through normalization. To test this idea, we characterized area summation and contrast response properties in V1 with and without feedback from V2 and V3 in alert macaques and applied a standard normalization model to the data. Area summation properties were well explained by a form of divisive normalization, which computes the ratio between a neuron's driving input and the spatially integrated activity of a “normalization pool.” Feedback inactivation reduced surround suppression by shrinking the spatial extent of the normalization pool. This effect was independent of the gain modulation thought to mediate the influence of contrast on area summation, which remained intact during feedback inactivation. Contrast sensitivity within the receptive field center was also unaffected by feedback inactivation, providing further evidence that feedback participates in normalization independent of the circuit mechanisms involved in modulating contrast gain and saturation. These results suggest that corticocortical feedback contributes to surround suppression by increasing the visuotopic extent of normalization and, via this mechanism, feedback can play a critical role in contextual information processing

Neuroanatomy goes viral!

The nervous system is complex not simply because of the enormous number of neurons it contains but by virtue of the specificity with which they are connected. Unraveling this specificity is the task of neuroanatomy. In this endeavor, neuroanatomists have traditionally exploited an impressive array of tools ranging from the Golgi method to electron microscopy. An ideal method for studying anatomy would label neurons that are interconnected, and, in addition, allow expression of foreign genes in these neurons. Fortuitously, nature has already partially developed such a method in the form of neurotropic viruses, which have evolved to deliver their genetic material between synaptically connected neurons while largely eluding glia and the immune system. While these characteristics make some of these viruses a threat to human health, simple modifications allow them to be used in controlled experimental settings, thus enabling neuroanatomists to trace multi-synaptic connections within and across brain regions. Wild-type neurotropic viruses, such as rabies and alpha-herpes virus, have already contributed greatly to our understanding of brain connectivity, and modern molecular techniques have enabled the construction of recombinant forms of these and other viruses. These newly engineered reagents are particularly useful, as they can target genetically defined populations of neurons, spread only one synapse to either inputs or outputs, and carry instructions by which the targeted neurons can be made to express exogenous proteins, such as calcium sensors or light-sensitive ion channels, that can be used to study neuronal function. In this review, we address these uniquely powerful features of the viruses already in the neuroanatomist’s toolbox, as well as the aspects of their biology that currently limit their utility. Based on the latter, we consider strategies for improving viral tracing methods by reducing toxicity, improving control of transsynaptic spread, and extending the range of species that can be studied

Direct Imaging of Hippocampal Epileptiform Calcium Motifs Following Kainic Acid Administration in Freely Behaving Mice

Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). We observed that KA administration led to systematic patterns of epileptiform calcium activity: a series of large-scale, intensifying flashes of increased calcium fluorescence concurrent with a cluster of low-amplitude EEG waveforms. This was accompanied by a steady increase in cellular calcium levels (>5 fold increase relative to the baseline), followed by an intense spreading calcium wave characterized by a 218% increase in global mean intensity of calcium fluorescence (n = 8, range [114 - 349%], p<10-4; t-test). The wave had no consistent EEG phenotype and occurred before the onset of motor convulsions. Similar changes in calcium activity were also observed in animals treated with 2 different proconvulsant agents, N-methyl-D-aspartate (NMDA) and pentylenetetrazol (PTZ), suggesting the measured changes in calcium dynamics are a signature of seizure activity rather than a KA-specific pathology. Additionally, despite reducing the behavioral severity of KA-induced seizures, the anticonvulsant drug valproate (VA, 300 mg/kg) did not modify the observed abnormalities in calcium dynamics. These results confirm the presence of pathological calcium activity preceding convulsive motor seizures and support calcium as a candidate signaling molecule in a pathway connecting seizures to subsequent cellular damage. Integrating in vivo calcium imaging with traditional assessment of seizures could potentially increase translatability of pharmacological intervention, leading to novel drug screening paradigms and therapeutics designed to target and abolish abnormal patterns of both electrical and calcium excitation

Plasma Dynamics

Contains table of contents for Section 2 and reports on four research projects.National Science Foundation Grant ECS 89-02990U.S. Air Force - Office of Scientific Research Grant AFOSR 89-0082-BU.S. Army - Harry Diamond Laboratories Contract DAAL02-89-K-0084U.S. Department of Energy Contract DE-AC02-90ER40591U.S. Navy - Office of Naval Research Grant N00014-90-J-4130Lawrence Livermore National Laboratory Subcontract B-160456National Science Foundation Grant ECS 88-22475U.S. Department of Energy Contract DE-FG02-91-ER-54109National Aeronautics and Space Administration Grant NAGW-2048U.S.-Israel Binational Science Foundation Grant 87-0057U.S Department of Energy Contract DE-AC02-78-ET-5101

Plasma Dynamics

Contains table of contents for Section 2 and reports on four research projects.Lawrence Livermore National Laboratory Subcontract 6264005National Science Foundation Grant ECS 84-13173National Science Foundation Grant ECS 85-14517U.S. Air Force - Office of Scientific Research Contract AFOSR 84-0026U.S. Army - Harry Diamond Laboratories Contract DAAL02-86-C-0050U.S. Navy - Office of Naval Research Contract N00014-87-K-2001National Science Foundation Grant ECS 85-15032National Science Foundation Grant ECS 88-22475U.S. Department of Energy Contract DE-AC02-ET-5101

Speech Communication

Contains table of contents for Part IV, table of contents for Section 1, an introduction, reports on seven research projects and a list of publications.C.J. Lebel FellowshipDennis Klatt Memorial FundNational Institutes of Health Grant T32-DC00005National Institutes of Health Grant R01-DC00075National Institutes of Health Grant F32-DC00015National Institutes of Health Grant R01-DC00266National Institutes of Health Grant P01-DC00361National Institutes of Health Grant R01-DC00776National Science Foundation Grant IRI 89-10561National Science Foundation Grant IRI 88-05680National Science Foundation Grant INT 90-2471

Contributions of early parallel pathways to extrastriate visual cortex in macaque monkey

Parallel Processing is a commonly used strategy in sensory systems of the mammalian brain. In the primate visual system, information is relayed from the retina to primary visual cortex (V1) along three parallel pathways: magnocellular (M), parvocellular (P), and koniocellular (K). These three pathways remain anatomically and physiologically distinct as they pass through M, P, and K layers of the lateral geniculate nucleus (LGN) of the thalamus and into V1, with the M pathway terminating primarily in layer 4C[alpha] the P pathway in layer 4C[beta], and the K pathway in the cytochrome oxidase (CO) blobs of layer 2/3. Beyond V1, visual information is processed in relatively independent dorsal and ventral streams specialized for computations related to spatial vision and object recognition respectively. Understanding the relationship between early parallel pathways and dorsal and ventral cortical processing streams has proven difficult because of the substantial convergence of M, P, and K pathways outside of layer 4C of V1. We used rabies virus as both a mono- and trans-synaptic retrograde tracer to determine the contributions of M and P pathways to dorsal stream cortical area MT in macaque monkey. MT is specialized for motion and depth processing and is thought to be dominated by the M pathway, with little or no contribution from the P or K pathways. We first injected rabies virus into MT with a 3 day survival time, allowing virus to cross one synapse and infect cells disynaptic to the injection site. We found large numbers of parvalbumin- positive, calbindin-negative neurons retrogradely labeled in the M and P layers of the LGN, providing evidence for a disynaptic M and P input to MT, likely mediated by layer 6 Meynert cells in V1. We next analyzed V1 after the very same injections into MT and found disynaptic label in layer 4C to be confined almost exclusively to M-dominated layer 4C[alpha]. This indicated that the most direct ascending input through layer 4C of V1 to MT is dominated by the M pathway. In order to determine if MT receives indirect P input through layer 4C of V1, we made injections into MT once again, this time with a 6 day survival time, allowing the virus to spread up to four synapses past the cells that project directly to MT. In this case, we found transynaptic label throughout all layers of V1, including P-dominated layer 4C[beta], indicating that MT does receive indirect P inputs through layer 4C of V1. In order to determine the likely relay of this P input to MT, we made 3 day survival injections of virus into V3 and V2, areas that provide indirect inputs from layer 4B of V1 to MT. Only after certain injections into V2, but not V3, did we observe disynaptic label in both M and P sublayers of 4C. These results suggest that while the most direct ascending input through layer 4C of V1 to MT is dominated by the M pathway, within a few more synapses the P pathway contributes as well, likely through the CO thick stripes of V2. In a final set of experiments, we used a modified rabies virus that expresses green fluorescent protein and doesn't cross synapses to compare the detailed morphology of neurons projecting directly from V1 to MT or V2. We found that cells projecting from layer 4B of V1 to MT were a majority spiny stellate and those projecting to V2 were overwhelmingly pyramidal. Additionally, MT-projecting cells had larger cell bodies, more total dendritic length, and were located deeper within layer 4B. Finally, pyramidal cells projecting to MT were located preferentially underneath CO blobs, where they could receive strong M inputs onto their apical dendrites. These results suggest that specialized and distinct cell populations in layer 4B of V1 mediate an M- dominated signal to MT and a mixed M and P signal to V2. All together, these studies provide strong evidence for the existence of multiple circuits between LGN and MT. Each pathway receives a different combination of M and P inputs and is uniquely suited to convey visual information with varying degrees of spatial and temporal resolution, contrast sensitivity, and color selectivity. Distinct cell types underlie many of these circuits, overcoming the lack of spatial compartmentalization of V1 outputs. Functional studies that can target these specialized cell types and circuits will be necessary to elucidate the contributions of each pathway to response properties in MT and, ultimately, to visual perception and behavio

Data from: Optogenetically induced low-frequency correlations impair perception

Deployment of covert attention to a spatial location can cause large decreases in low-frequency correlated variability among neurons in macaque area V4 whose receptive-fields lie at the attended location. It has been estimated that this reduction accounts for a substantial fraction of the attention-mediated improvement in sensory processing. These estimates depend on assumptions about how population signals are decoded and the conclusion that correlated variability impairs perception, is purely hypothetical. Here we test this proposal directly by optogenetically inducing low-frequency fluctuations, to see if this interferes with performance in an attention-demanding task. We find that low-frequency optical stimulation of neurons in V4 elevates correlations among pairs of neurons and impairs the animal's ability to make fine sensory discriminations. Stimulation at higher frequencies does not impair performance, despite comparable modulation of neuronal responses. These results support the hypothesis that attention-dependent reductions in correlated variability contribute to improved perception of attended stimuli

Head-mounted microendoscopic calcium imaging in dorsal premotor cortex of behaving rhesus macaque.

Microendoscopic calcium imaging with one-photon miniature microscopes enables unprecedented readout of neural circuit dynamics during active behavior in rodents. In this study, we describe successful application of this technology in the rhesus macaque, demonstrating plug-and-play, head-mounted recordings of cellular-resolution calcium dynamics from large populations of neurons simultaneously in bilateral dorsal premotor cortices during performance of a naturalistic motor reach task. Imaging is stable over several months, allowing us to longitudinally track individual neurons and monitor their relationship to motor behavior over time. We observe neuronal calcium dynamics selective for reach direction, which we could use to decode the animal's trial-by-trial motor behavior. This work establishes head-mounted microendoscopic calcium imaging in macaques as a powerful approach for studying the neural circuit mechanisms underlying complex and clinically relevant behaviors, and it promises to greatly advance our understanding of human brain function, as well as its dysfunction in neurological disease

Head-mounted microendoscopic calcium imaging in dorsal premotor cortex of behaving rhesus macaque.

Microendoscopic calcium imaging with one-photon miniature microscopes enables unprecedented readout of neural circuit dynamics during active behavior in rodents. In this study, we describe successful application of this technology in the rhesus macaque, demonstrating plug-and-play, head-mounted recordings of cellular-resolution calcium dynamics from large populations of neurons simultaneously in bilateral dorsal premotor cortices during performance of a naturalistic motor reach task. Imaging is stable over several months, allowing us to longitudinally track individual neurons and monitor their relationship to motor behavior over time. We observe neuronal calcium dynamics selective for reach direction, which we could use to decode the animal's trial-by-trial motor behavior. This work establishes head-mounted microendoscopic calcium imaging in macaques as a powerful approach for studying the neural circuit mechanisms underlying complex and clinically relevant behaviors, and it promises to greatly advance our understanding of human brain function, as well as its dysfunction in neurological disease