PROJECT SUMMARY/ ABSTRACT
Although smoothly linking individual actions into sequences is critical for execution of complex behaviors, we
still have a limited understanding of how behavioral sequences are encoded in the brain. Accumulating
evidence suggests that striatal activity patterns are linked to performance of sequenced behaviors, but the
role of cortical inputs in their initiation and control is less clear. We therefore used the SAPAP3-knockout
(KO) mouse experimental system, which displays repetitive grooming behavior associated with central
striatal (CS) hyperactivity, to investigate how cortical and striatal regions interact to generate both normal
and perseverative action patterns. In our recent work, we demonstrated that SAPAP3-KOs do not have
abnormalities in striatal intrinsic properties using ex vivo electrophysiology. However, we observed large (~6
fold) increases in extrinsic drive to CS from the major cortical input to this region: anterolateral motor area
(ALM- also known as M2). (Corbit et al, 2019). These results suggested that repeated selection of motor
programs could be caused by excessive drive from ALM, an area whose human homologues (SMA/pre-
SMA) have been linked to Tourette Syndrome (TS) and OCD. Our preliminary optogenetics and
photometry data support this theory by identifying ALM activity that ramps up during grooming, and
terminates at grooming bout cessation. Together, these results indicate that ALM may be a key under-
recognized hub for the regulation of innate sequenced behaviors. However, 1) this idea has not yet
been rigorously tested, and 2) it is unclear if the same principles apply to learned sequenced behaviors.
Here we will use state-dependent optogenetics, ex vivo electrophysiology, and longitudinal in vivo Ca+2
imaging to determine the role of ALM in the generation of normal and abnormal innate and learned
sequenced behaviors. In Aim 1, we will Identify the ALM ensemble responsible for grooming-associated
ramping activity. In Aim 2, we will determine whether increasing ALM-CS drive leads to repeated selection
of innate and/or learned sequenced behaviors. In Aim 3, we will define the role of ALM activity during
performance of learned sequences using in vivo microscopy and optogenetics. The goal of these studies is
to determine how cortico-striatal circuits control the assembly of individual actions into organized sequences,
which could ultimately lead to new neurostimulation-based treatment targets for perseverative behaviors.
