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.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/13129563 |
| Date | 23 October 2014 |
| Creators | Saunders, Arpiar Bruce |
| Contributors | Sabatini, Bernardo Luis |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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