January 10, 2017

Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls

PI: Kent Berridge, PhD

This project builds on Dr. Martin Sarter’s published and preliminary work dissecting the mechanisms of the detection of relevant cues, transfer of this information to striatum, and its integration with ongoing motor processing. Based on the Sarter team’s demonstration of a role for basal forebrain cholinergic projections in the DL (dual lesion) rodent model of PD falling, this project uses optogenetic techniques to test the hypothesis that an enhanced fall propensity can be caused specifically by the loss of fast cholinergic signaling (i.e., “transients”) known to mediate attention. Additional experiments define how cholinergic-mediated cortical attentional information is integrated with motor selection processes. Frontostriatal circuitry (glutamatergic corticostriatal projections) is essential for action planning, particularly when habit-guided action is disrupted and task shifts are needed. Such adjustment depends critically on corticostriatal information transfer to guide adaptive movement selection and sequencing. Deficient cortical cholinergic activity impairs attentional shifts toward alternative actions, uncoupling striatal action selection from goals, causing ill-timed or absent responses. Guided by this framework, intrinsic to the AMI model, Dr. Sarter’s team acquired compelling preliminary data detecting the signals encoding attentional information transferred to the striatum (via corticostriatal terminals), where it is hypothesized to be integrated with vigor and kinematic signals supplied by nigrostriatal dopaminergic terminals. Utilizing a novel behavioral paradigm, they demonstrate that a cue instructing the animal to turn evokes a time-locked increase of striatal glutamate (that will be shown to originate from corticostriatal afferents), and a similarly timed burst of acetylcholine from cholinergic neurons. Dr. Sarter’s former team, now under the direction of Dr. Berridge, is specifically testing the hypothesis that this integrative function is essential for complex motor control, including PD gait dysfunction. Preliminary findings strongly support a role for cholinergic signals in integrating the attentional and motor signals during gait; chemogenetic activation of these neurons reduces fall propensity in DL rats (often preceded by freezing-like motor behaviors in the animals), whereas their inhibition in intact animals mimics DL-type falls. These data support key aspects of the AMI model by implicating cholinergic neurotransmission at two successive nodes along the cortico-striatal pathway critical to support the attentional-motor interface – in cortex for signal detection, and in striatum for signal integration. These studies will identify key substrates of attentional-motor integration in the AMI.