Final Report Summary - BURSTPAUSEPLASTICITY (Plasticity of the Burst-Pause Response in the Tonically Active Cholinergic Interneurons of the Striatum in Normal and Parkinsonian Mice)
The capacity to redirect attention and assign motivational value to novel stimuli in our ever-changing environment depends on the excitatory (glutamatergic) projection from the parafascicular (PF) nucleus of the thalamus to the striatum. The assignment of value takes the form of a burst-pause (B-P) sequence that interrupts the tonic firing of striatal cholinergic interneurons (ChIs) that are targets of this projection. The B-P response is a neural correlate of classical conditioning, in the sense that its size (eg, the length of the pause) changes with conditioning. The objectives of the current study are i) to characterize the biophysical mechanism underlying the B-P response of ChIs (both in terms of their intrinsic cellular properties and the role of afferent synaptic effect); ii) to determine what cellular adaptations give rise to the plasticity of the B-P response; iii) to study how this plasticity impacts striatal function; iv) to explain the dopamine dependency of the B-P response, and to provide insight into how it can be restored after dopamine depletion.
Our initial observation demonstrated a putative mechanism for the plasticity of the B-P response in the form of the augmentation of the current underlying the slow afterhyperpolarization observed in ChIs. During the first two years of the project we established and refined two animal models for selective activation of cortical vs. thalamic input to ChIs, respectively. However, replicating the initial finding proved challenging, so we adopted alternative strategies. Instead of focusing on the plasticity of the B-P response, we focused on synaptic transmission that gives rise to the response. This work led to a published manuscript about difference between cortical and thalamic synaptic transmission to ChIs both in control and in experimental parkinsonism. Some of the data collected were also included in another manuscript about ChIs in Huntington's disease.
During the first years of funding, I secured substantial extramural funding for my nascent laboratory, most notably, a 2M Euro ERC Consolidator grant. The grant itself funded the above experiments and publication, but during the life of this grant I recruited and trained 2 postdocs, two PhD students, two MSc students, a lab manager and a research associate. I am currently up for tenure with 6 publications (in excellent journals, two more submitted),two invited reviews and a few book chapters.
Our initial observation demonstrated a putative mechanism for the plasticity of the B-P response in the form of the augmentation of the current underlying the slow afterhyperpolarization observed in ChIs. During the first two years of the project we established and refined two animal models for selective activation of cortical vs. thalamic input to ChIs, respectively. However, replicating the initial finding proved challenging, so we adopted alternative strategies. Instead of focusing on the plasticity of the B-P response, we focused on synaptic transmission that gives rise to the response. This work led to a published manuscript about difference between cortical and thalamic synaptic transmission to ChIs both in control and in experimental parkinsonism. Some of the data collected were also included in another manuscript about ChIs in Huntington's disease.
During the first years of funding, I secured substantial extramural funding for my nascent laboratory, most notably, a 2M Euro ERC Consolidator grant. The grant itself funded the above experiments and publication, but during the life of this grant I recruited and trained 2 postdocs, two PhD students, two MSc students, a lab manager and a research associate. I am currently up for tenure with 6 publications (in excellent journals, two more submitted),two invited reviews and a few book chapters.