Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior

Abstract

Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (ϳ3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (ϳ6-fold) in strength and reliability in KOs relative to WTs. These results suggest that increased M2-striatal drive may contribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.These findings highlight an unexpected contribution of M2 projections to striatal dysfunction in the Sapap3-KO obsessivecompulsive disorder (OCD)-relevant mouse model, with M2 inputs strengthened by at least sixfold onto both spiny projection neurons and fast-spiking interneurons in central striatum. Because M2 is thought to be homologous to presupplementary/ supplementary motor areas (pre-SMA/SMA) in humans, regions important for movement preparation and behavioral sequencing, these data are consistent with a model in which increased drive from M2 leads to excessive selection of sequenced motor patterns. Together with observations of hyperactivity in pre-SMA/SMA in both OCD and Tourette syndrome, and evidence that pre-SMA is a potential target for repetitive transcranial magnetic stimulation treatment in OCD, these results support further dissection of the role of M2 in compulsivity.

Dissociable roles of central striatum and anterior lateral motor area in initiating and sustaining naturalistic behavior

“…Interestingly, this positions central striatum (CS) at a crucial nexus of corticostriatal inputs along this topography (Ebrahimi et al, 1992;Oh et al, 2014), making it well suited to link motivational factors and sensorimotor responses. Consistent with this idea, in prior work we demonstrated that CS receives projections from both lateral orbitofrontal cortex (LOFC) and anterior lateral motor area (ALM) (Corbit 2019), regions implicated in behavioral flexibility (Kim and Ragozzino, 2005) and motor preparation (Guo et al, 2014;Li et al, 2015), respectively. Furthermore, early studies showed that activating central regions of striatum via disinhibition with picrotoxin caused tic-like behavior in rodents (Tarsy et al, 1978).…”

“…Prior work has demonstrated that anterior M2/anterior lateral motor area (ALM), one of the major cortical inputs to CS (Corbit et al, 2019), is associated both with appropriate sequencing of movements during trained tasks and with generating licking movements (Bollu et al, 2019;Li et al, 2015;Rothwell et al, 2015). ALM may therefore be uniquely suited for guiding selection of spontaneously generated behaviors such as body grooming.…”

“…Understanding how corticostriatal circuits mediate behavioral selection and initiation in a naturalistic setting is critical to understanding how the brain chooses and executes behavior in unconstrained situations. Central striatum (CS), an understudied region that lies in the middle of the motor-limbic topography, is well-poised to play an important role in these processes since its main cortical inputs (Corbit et al, 2019) have been implicated in behavioral flexibility (lateral orbitofrontal cortex (Kim and Ragozzino, 2005)) and response preparation (anterior lateral motor area, ALM) (Li et al, 2015), However, although CS activity has been associated with conditioned grooming behavior in transgenic mice (Burguiere et al, 2013), the role of CS and its cortical inputs in the selection of spontaneous behaviors has not been explored. We therefore studied the role of CS corticostriatal circuits in behavioral selection in an open field context.…”

NINscope: a versatile miniscope for multi-region circuit investigations

“…The opsin ChrimsonR was transduced in either of the two cortical regions and a 625 nm LED implanted above the cortex ( Figure 6A ). In reduced preparations, OFC and M2 have both been found to regulate the activity of neurons in specific DS regions (Corbit et al, 2019) , with the impact of OFC on DS being stronger than that of M2. We sought to confirm these findings in freely behaving mice.…”

Individual differences in stereotypy and neuron subtype translatome with TrkB deletion

“…Activation of striatal dopamine D1 receptors induces stereotypies in non-human animals 7 , including those with dopamine deficiency 8 and hyperdopaminergic function 9 , implicating a dysregulated direct-pathway in stereotypy behavior. Similarly, TS and OCD patients display increased sensitivity of striatal dopamine receptors and downregulation of D1 receptors 10,11 likely contributing to striatal hyperactivity 6, 12 . Additionally, mutations in genes regulating synaptic function and dendritic growth occur in TS, OCD and ASD [13][14][15][16][17] and have been confirmed by striatal transcriptome analyses in TS and OCD patients 18,19 . Thus, impaired MSN morphology combined with disrupted physiological properties may underlie neuronal hyperactivity and/or dopamine hypersensitivity and ultimately altered direct pathway output 8 .…”