2 research outputs found
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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
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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