How Structure Determines Correlations in Neuronal Networks

Networks are becoming a ubiquitous metaphor for the understanding of complex biological systems, spanning the range between molecular signalling pathways, neural networks in the brain, and interacting species in a food web. In many models, we face an intricate interplay between the topology of the network and the dynamics of the system, which is generally very hard to disentangle. A dynamical feature that has been subject of intense research in various fields are correlations between the noisy activity of nodes in a network. We consider a class of systems, where discrete signals are sent along the links of the network. Such systems are of particular relevance in neuroscience, because they provide models for networks of neurons that use action potentials for communication. We study correlations in dynamic networks with arbitrary topology, assuming linear pulse coupling. With our novel approach, we are able to understand in detail how specific structural motifs affect pairwise correlations. Based on a power series decomposition of the covariance matrix, we describe the conditions under which very indirect interactions will have a pronounced effect on correlations and population dynamics. In random networks, we find that indirect interactions may lead to a broad distribution of activation levels with low average but highly variable correlations. This phenomenon is even more pronounced in networks with distance dependent connectivity. In contrast, networks with highly connected hubs or patchy connections often exhibit strong average correlations. Our results are particularly relevant in view of new experimental techniques that enable the parallel recording of spiking activity from a large number of neurons, an appropriate interpretation of which is hampered by the currently limited understanding of structure-dynamics relations in complex networks

Post hoc immunostaining of GABAergic neuronal subtypes following in vivo two-photon calcium imaging in mouse neocortex

GABAergic neurons in the neocortex are diverse with regard to morphology, physiology, and axonal targeting pattern, indicating functional specializations within the cortical microcircuitry. Little information is available, however, about functional properties of distinct subtypes of GABAergic neurons in the intact brain. Here, we combined in vivo two-photon calcium imaging in supragranular layers of the mouse neocortex with post hoc immunohistochemistry against the three calcium-binding proteins parvalbumin, calretinin, and calbindin in order to assign subtype marker profiles to neuronal activity. Following coronal sectioning of fixed brains, we matched cells in corresponding volumes of image stacks acquired in vivo and in fixed brain slices. In GAD67-GFP mice, more than 95% of the GABAergic cells could be unambiguously matched, even in large volumes comprising more than a thousand interneurons. Triple immunostaining revealed a depth-dependent distribution of interneuron subtypes with increasing abundance of PV-positive neurons with depth. Most importantly, the triple-labeling approach was compatible with previous in vivo calcium imaging following bulk loading of Oregon Green 488 BAPTA-1, which allowed us to classify spontaneous calcium transients recorded in vivo according to the neurochemically defined GABAergic subtypes. Moreover, we demonstrate that post hoc immunostaining can also be applied to wild-type mice expressing the genetically encoded calcium indicator Yellow Cameleon 3.60 in cortical neurons. Our approach is a general and flexible method to distinguish GABAergic subtypes in cell populations previously imaged in the living animal. It should thus facilitate dissecting the functional roles of these subtypes in neural circuitry

Entry of Herpes Simplex Virus Type 1 (HSV-1) into the Distal Axons of Trigeminal Neurons Favors the Onset of Nonproductive, Silent Infection

Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants. By contrast, selective application of the virus to distal axons led to a largely nonproductive infection that was characterized by the poor expression of lytic genes and the presence of high levels of the 2.0-kb major latency-associated transcript (LAT) RNA. Treatment of the explants with the immediate-early (IE) gene transcriptional inducer hexamethylene bisacetamide, and simultaneous co-infection of the GC with HSV-1, herpes simplex virus type 2 (HSV-2) or pseudorabies virus (PrV) helper virus significantly enhanced the ability of HSV-1 to productively infect sensory neurons upon axonal entry. Helper-virus-induced transactivation of HSV-1 IE gene expression in axonally-infected TGEs in the absence of de novo protein synthesis was dependent on the presence of functional tegument protein VP16 in HSV-1 helper virus particles. After the establishment of a LAT-positive silent infection in TGEs, HSV-1 was refractory to transactivation by superinfection of the GC with HSV-1 but not with HSV-2 and PrV helper virus. In conclusion, the site of entry appears to be a critical determinant in the lytic/latent decision in sensory neurons. HSV-1 entry into distal axons results in an insufficient transactivation of IE gene expression and favors the establishment of a nonproductive, silent infection in trigeminal neurons

Activity in a premotor cortical nucleus of zebra finches is locally organized and exhibits auditory selectivity in neurons but not in glia

Motor functions are often guided by sensory experience, most convincingly illustrated by complex learned behaviors. Key to sensory guidance in motor areas may be the structural and functional organization of sensory inputs and their evoked responses. We study sensory responses in large populations of neurons and neuron-assistive cells in the songbird motor area HVC, an auditory-vocal brain area involved in sensory learning and in adult song production. HVC spike responses to auditory stimulation display remarkable preference for the bird's own song (BOS) compared to other stimuli. Using two-photon calcium imaging in anesthetized zebra finches we measure the spatio-temporal structure of baseline activity and of auditory evoked responses in identified populations of HVC cells. We find strong correlations between calcium signal fluctuations in nearby cells of a given type, both in identified neurons and in astroglia. In identified HVC neurons only, auditory stimulation decorrelates ongoing calcium signals, less for BOS than for other sound stimuli. Overall, calcium transients show strong preference for BOS in identified HVC neurons but not in astroglia, showing diversity in local functional organization among identified neuron and astroglia populations

Differential connectivity and response dynamics of excitatory and inhibitory neurons in visual cortex

Neuronal responses during sensory processing are influenced by both the organization of intracortical connections and the statistical features of sensory stimuli. How these intrinsic and extrinsic factors govern the activity of excitatory and inhibitory populations is unclear. Using two-photon calcium imaging in vivo and intracellular recordings in vitro, we investigated the dependencies between synaptic connectivity, feature selectivity and network activity in pyramidal cells and fast-spiking parvalbumin-expressing (PV) interneurons in mouse visual cortex. In pyramidal cell populations, patterns of neuronal correlations were largely stimulus-dependent, indicating that their responses were not strongly dominated by functionally biased recurrent connectivity. By contrast, visual stimulation only weakly modified co-activation patterns of fast-spiking PV cells, consistent with the observation that these broadly tuned interneurons received very dense and strong synaptic input from nearby pyramidal cells with diverse feature selectivities. Therefore, feedforward and recurrent network influences determine the activity of excitatory and inhibitory ensembles in fundamentally different ways