Circuit interactions between the cortex and basal ganglia

All animals must adapt their behaviors by experience to survive. In mammals, this adaptive process is thought occur through a synaptic loop involving the cortex, basal ganglia (BG) and thalamus. Here we use transgenic mice and novel recombinant viruses (Chapter 1) to explore the brain circuits that underlie this interaction. Our focus is on how cell types within the BG affect cortical feedback during development and in adulthood. Accepted models postulate that the BG modulate cerebral cortex 1) indirectly via an inhibitory output to thalamus and that this thalamic output is 2) bi-directionally controlled from within the BG by striatal direct (dSPNs) and indirect (iSPNs) pathway spiny neurons. In Chapter 2, we show that activity in iSPNs and dSPNs plays a complementary role in the post-natal synaptic wiring of the BG. Inhibiting iSPNs or dSPNs results in opposite changes in the number of excitatory synapses made onto SPNs from cortical and thalamic inputs. Our results suggest that the cortex-BG-thalamus function in a closed-loop and balanced iSPN/dSPN activity is required for proper synaptic wiring during development. In Chapter 3, we describe a non-thalamic output of the BG to the frontal cortex (FC) emanating from globus pallidus externus (GP). The GP-FC projection consists of two cell types that release GABA and GABA/Acetylcholine, mostly onto cortical interneurons, with the net effect of increasing cortical firing rate. These results suggest that iSPNs and dSPNs can affect cortical output through GP-based disinhibition in addition to thalamus-based excitation. Moreover, GP-FC cells provide a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the BG yet modulate activity in FC. The presence of a direct BG output to cortex extends the looped architecture through which the cortex-BG-thalamus control adaptive behavior and can become dysregulated to cause disease. Together our thesis results support the phenomenology of the BG pathway model, but suggest a major revision to the underlying circuitry

Recurrent network activity drives striatal synaptogenesis

Neural activity during development critically shapes postnatal wiring of the mammalian brain. This is best illustrated by the sensory systems, in which the patterned feed-forward excitation provided by sensory organs and experience drives the formation of mature topographic circuits capable of extracting specific features of sensory stimuli1,2. In contrast, little is known about the role of early activity in the development of the basal ganglia, a phylogenetically ancient group of nuclei fundamentally important for complex motor action and reward-based learning3,4. These nuclei lack direct sensory input and are only loosely topographically organized5,6, forming interlocking feed-forward and feed-back inhibitory circuits without laminar structure. Here we use transgenic mice and viral gene transfer methods to modulate neurotransmitter release and neuronal activity in vivo in the developing striatum. We find that the balance of activity among the two inhibitory and antagonist pathways in the striatum regulates excitatory innervation of the basal ganglia during development. These effects indicate that the propagation of activity through a multi-stage network regulates the wiring of the basal ganglia, revealing an important role of positive feedback in driving network maturation

Vesicular Stomatitis Virus with the Rabies Virus Glycoprotein Directs Retrograde Transsynaptic Transport Among Neurons In Vivo

Defining the connections among neurons is critical to our understanding of the structure and function of the nervous system. Recombinant viruses engineered to transmit across synapses provide a powerful approach for the dissection of neuronal circuitry in vivo. We recently demonstrated that recombinant vesicular stomatitis virus (VSV) can be endowed with anterograde or retrograde transsynaptic tracing ability by providing the virus with different glycoproteins. Here we extend the characterization of the transmission and gene expression of recombinant VSV (rVSV) with the rabies virus glycoprotein (RABV-G), and provide examples of its activity relative to the anterograde transsynaptic tracer form of rVSV. rVSV with RABV-G was found to drive strong expression of transgenes and to spread rapidly from neuron to neuron in only a retrograde manner. Depending upon how the RABV-G was delivered, VSV served as a polysynaptic or monosynaptic tracer, or was able to define projections through axonal uptake and retrograde transport. In animals co-infected with rVSV in its anterograde form, rVSV with RABV-G could be used to begin to characterize the similarities and differences in connections to different areas. rVSV with RABV-G provides a flexible, rapid, and versatile tracing tool that complements the previously described VSV-based anterograde transsynaptic tracer

Neuromodulation of excitatory synaptogenesis in striatal development

Dopamine is released in the striatum during development and impacts the activity of Protein Kinase A (PKA) in striatal spiny projection neurons (SPNs). We examined whether dopaminergic neuromodulation regulates activity-dependent glutamatergic synapse formation in the developing striatum. Systemic in vivo treatment with Gαs-coupled G-protein receptors (GPCRs) agonists enhanced excitatory synapses on direct pathway striatal spiny projection neurons (dSPNs), whereas rapid production of excitatory synapses on indirect pathway neurons (iSPNs) required the activation of Gαs GPCRs in SPNs of both pathways. Nevertheless, in vitro Gαs activation was sufficient to enhance spinogenesis induced by glutamate photolysis in both dSPNs and iSPNs, suggesting that iSPNs in intact neural circuits have additional requirements for rapid synaptic development. We evaluated the in vivo effects of enhanced glutamate release from corticostriatal axons and postsynaptic PKA and discovered a mechanism of developmental plasticity wherein rapid synaptogenesis is promoted by the coordinated actions of glutamate and postsynaptic Gαs-coupled receptors. DOI: http://dx.doi.org/10.7554/eLife.10111.00

Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.

Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states-including chemokine-enriched inflammatory microglia-persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease

Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types.

We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals

Linguistic Phylogenetics of the Austronesian Family: A Performance Review of Methods Adapted from Biology

Four methods for inferring biological phylogenies were applied to lexical and structural data of a representative sample of the Austronesian Family of languages. After introducing individual languages and the Family as a whole, each combination of method and data type is performance reviewed through topological comparison with a 'known' tree. The results suggest a two-step method which is described in detail. First, NeighborNet analysis is used to qualitatively assess how "phylogenetic" the data are and thus if tree building is justified. Next, Bayesian analysis is used to construct a tree. Under the proposed method, a combined lexical and structural data set produced a fully historically accurate tree, thus supporting past research through an alternative method. The increase in accuracy with combined data suggest that inferring the natural history of the whole language depends on reconciling the phylogenetic signals from component parts; a tension between the lexicon and structures with traceable correlates in both methods. Lastly, the evolutionary association of structural features is assessed. This result highlights the potential productivity of using biological methods to pursue previously untenable questions about language evolution

Silenced gustatory inputs reveal new populations of pheromone detection cells involved in Drosophila courtship and support a non-associative basis for courtship conditioning

Male Drosophila suppress courtship toward virgin females after an unproductive sexual encounter with a mated female. This learned behavior is mediated by pheromones and has been formalized as associative learning in a paradigm called courtship conditioning. To identify the neural machinery responsible, four populations of gustatory receptor neurons (GRNs) were functionally silenced during the male's initial training or subsequent test experience. While silencing all four populations reduced hard-wired courtship toward virgin females, behavioral differences arose when GRNs were silenced during training versus testing, or when males courted flies with different pheromone blends. Thus individual GRNs within a population control different aspects of behavior; a result which parallels the organization and drive of other gustatory behaviors like feeding and avoidance. To identify potential courtship circuits within the populations silenced, the behavioral results were compared across courtship contexts to generate "courtship channels:" hypothetical pathways connecting courtship behaviors to sub-sets of GRNs. One channel identified suggests courtship conditioning may not be associative in the classical formulation: males with this channel silenced during training suppress courtship selectively depending on the pheromones encountered during testing.\ud An alternative theory, called the "independent channel" model, explains this and other long-standing anomalous results by proposing that courtship suppression is produced by experience modifying the efficacy of individual courtship channels to drive courtship

How to use typological databases in historical linguistic research. Diachronica 24

Several databases have been compiled with the aim of documenting the distribution of typological features across the world&apos;s languages. is paper looks at ways of utilizing this type of data for making inferences concerning genealogical relationships by using phylogenetic algorithms originally developed for biologists. e focus is on methodology, including how to assess the stability of individual typological features and the suitability of di erent phylogenetic algorithms, as well as ways to enhance phylogenetic signals and heuristic procedures for identifying genealogical relationships. e various issues are illustrated by a small sample of empirical data from a set of Native American languages

Silenced gustatory inputs reveal new populations of pheromone detection cells involved in Drosophila courtship and support a non-associative basis for courtship conditioning

Male Drosophila suppress courtship toward virgin females after an unproductive sexual encounter with a mated female. This learned behavior is mediated by pheromones and has been formalized as associative learning in a paradigm called courtship conditioning. To identify the neural machinery responsible, four populations of gustatory receptor neurons (GRNs) were functionally silenced during the male\u27s initial training or subsequent test experience. While silencing all four populations reduced hard-wired courtship toward virgin females, behavioral differences arose when GRNs were silenced during training versus testing, or when males courted flies with different pheromone blends. Thus individual GRNs within a population control different aspects of behavior; a result which parallels the organization and drive of other gustatory behaviors like feeding and avoidance. To identify potential courtship circuits within the populations silenced, the behavioral results were compared across courtship contexts to generate courtship channels: hypothetical pathways connecting courtship behaviors to sub-sets of GRNs. One channel identified suggests courtship conditioning may not be associative in the classical formulation: males with this channel silenced during training suppress courtship selectively depending on the pheromones encountered during testing. An alternative theory, called the independent channel model, explains this and other long-standing anomalous results by proposing that courtship suppression is produced by experience modifying the efficacy of individual courtship channels to drive courtship