Accepted Manuscript Title: Back to the Future: Circuit-Testing TS and OCD Author: Frank H. Burton PII: S0165-0270(17)30269-8 DOI: http://dx.doi.org/doi:10.1016/j.jneumeth.2017.07.025 Reference: NSM 7801 To appear in: Journal of Neuroscience Methods Received date: 25-1-2017 Revised date: 3-7-2017 Accepted date: 25-7-2017 Please cite this article as: Burton Frank H.Back to the Future: Circuit-Testing TS and OCD.Journal of Neuroscience Methods http://dx.doi.org/10.1016/j.jneumeth.2017.07.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Article Type: Review Article Back to the Future: Circuit-Testing TS & OCD Running Title: Brain Circuit-Testing TS & OCD Frank H. Burtona,b aDepartment of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis MN 55455-0217 USA bMinneapolis Medical Research Foundation, Hennepin County Medical Center, 701 Park Ave, Shapiro S3.111, Minneapolis MN 55415-1623 USA Author Correspondence: Frank H. Burton, Ph.D., Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street S.E., Minneapolis MN 55455-0217 USA; Tel/V-mail: +1-612-873-6895; E-mail: [email protected] 1 TS & OCD CTX Circuit-Tests AMY Chronic Neuropotentiation GLU Photic Neurostimulation FSI Chemogenetic Neuropotentiation ACH DA Activity-Dependent D2 D1 Chemogenetic Neurostimulation STR STR Chemogenetic Neuroblockade IP DP Photic Neuroinhibition SNc Chemogenetic Neuroinhibition Activity-Dependent Chemogenetic Neuroinhibition “URGE / MOVE” Highlights • The first transgenic circuit-test 20 years ago was also the first model of TS & OCD. • This “Ticcy” mouse model has D1+ neuropotentiated corticostriatal glutamate output. • TS- & OCD-like sensorimotor gating & gait disorders were newly shown in these mice. • Chemogenetics & optogenetics are further defining these TS- & OCD-like CSTC circuits. • Activity-dependent chemogenetics may in the next 20 years explain (& treat) TS & OCD. Abstract A decade before the rise of optogenetics, the first behavioral “circuit-test” -- transgenically modulating the output of a genetically-specified brain circuit element to examine its effect on behavior -- was performed. The behaviors emulated in those mice were comorbid tics and compulsions, elicited by a gene borrowed from cholera bacteria and tailored to intracellularly neuropotentiate glutamatergic somatosensory cortical and limbic output neurons of cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Two decades later, cutting-edge chemogenetic and optogenetic methods are again being devoted to further characterize the circuits thought to trigger, mediate, aggravate, or ameliorate TS & OCD symptoms. These tour de force studies support essential roles in tics and compulsions for topographically-parallel corticostriatal and amygdalar glutamatergic output neurons; their target dorsal striatal & ventral striatal (nucleus accumbens) medium spiny neurons (MSNs) of the direct striatothalamic (urge & motor activating) vs. indirect striatopallidal (urge & motor suppressing) output pathways; and their converging modulatory dopaminergic and histaminergic afferents. Going “back to the future” to circuit-map tics and compulsions will give us precision targets for future psychological, drug, medtech, and gene therapies; look for “dopamine bypasses” on your next trip in the DeLorean. Abbreviations: ACH (acetylcholine); AMY; amygdala; cAMP, 3',5'-cyclic adenosine monophosphate; CSTC, cortico/amygdalo-striato-thalamo-cortical; CT, cholera toxin; CTX, cortex; D1, dopamine receptor subtype 1; D1+, D1 receptor-expressing; D1CT-7, Dopamine receptor D1 gene (DRD1)-promoter/cholera toxin A1 subunit transgenic sub-strain 7 mouse; D2+, dopamine D2 2 receptor subtype-expressing; DA, dopamine; DP, striatal direct pathway; DREADD, designer receptor exclusively activated by designer drug; E-SARE, enhanced synaptic activity-responsive element; FSIs, striatal fast spiking interneurons; GABA, gamma-amino butyric acid; Gi, inhibitory G- protein; GLU, glutamate; GPC, G-protein coupled; GPCR, G-protein coupled receptor; Gs, Gs/olf, Gq, stimulatory G-proteins; IP, striatal indirect pathway; MSNs, striatal medium spiny neurons; NPY, neuropeptide Y; NAc, nucleus accumbens; OCD; obsessive-compulsive disorder; OFC (orbitofrontal cortex); PPI (prepulse inhibition); SNc, substantia nigra pars compacta; STN, subthalamic nucleus; STR, striatum or striatal; TS, Tourette's syndrome; TTM, trichotillomania. Keywords: Tourette; compulsion; glutamate; transgenic; optogenetic; chemogenetic 1. Introduction The often comorbid tics and compulsions in Tourette’s syndrome (TS) and Obsessive- Compulsive Disorder (OCD) may involve overlapping or parallel brain circuits (Robertson, 2000; American Psychiatric Association, 2013). A role for cortical and amygdalar glutamatergic output subcircuits of CSTC loops in eliciting or mediating neurogenic tics and compulsions was proposed late last century, then elaborated in the intervening two decades (Campbell et al., 1999a, 1999b; McGrath et al., 2000; Carlsson, 2000; Rosenberg et al., 2000; Nordstrom and Burton, 2002; Singer et al., 2010; Milad and Rauch, 2012; Nordstrom et al., 2015). Functional MRI of TS 3 shows primary hyperactivity of excitatory somatosensory, insular and efferent motor output circuits, which elicits premonitory urges and tics (Bohlhalter et al., 2006; Wang et al., 2011), and secondary hypoactivity of motor-suppressing executive-control circuits (Swerdlow and Sutherland, 2005). The latter may include depletion or deficiency of these regulatory interneuron populations: 1) cortical GABAergic inhibitory interneurons; 2) striatal (STR) cholinergic interneurons that normally excite GABAergic STR “indirect pathway” (IP) medium spiny neurons (MSNs) suppressing tics and compulsions; and 3) STR parvalbumin-positive GABAergic fast-spiking interneurons (FSIs) that normally inhibit GABAergic STR “direct pathway” (DP) MSNs activating tics and compulsions (Kalanithi et al., 2005; Kataoka et al., 2010; Burguiere et al., 2013; Xu et al., 2015a). The frequent comorbidity of TS and OCD suggests their symptoms overlap not only in their interconnecting and parallel CSTC circuitry but also in their pathophysiology: Compulsions are usually preceded by obsessions and anxiety and involve orbitofrontal cortex (OFC) & amygdalar hyperactivity, while tics are preceded by discomfiting premonitory sensations & urges and involve OFC-interconnected somatosensory cortex & amygdalar hyperactivity; also, both show impaired sensorimotor gating, which normally filters out irrelevant inputs (Godar and Bortolato, 2017). Consequently, both OCD and TS involve hyper-attentiveness to the obsessions and/or urges, which are temporarily alleviated by performing the desired acts and/or motions, likely by feedback inhibition from prefrontal & motor cortex collaterals. Stress also aggravates both disorders, likely from hyperglutamatergic amygdalocortical output (Godar and Bortolato, 2017). Maladaptive habits also develop in both disorders, likely from overlap and parallelism of their CSTC circuitry, including their cortical & amygdalar elements and target dorsal striatum (STR) & ventral STR (nucleus accumbens, or NAc) elements, which modulate not only motor 4 activity but urges, aversion vs. reward, and habit formation (Bortolato and Pittenger, 2017). Consistent with their parallel neuropathophysiology, both TS and OCD are associated with hyperactivity of regional (somatosensory or orbitofrontal) cortical output neurons, and deficient cortical inhibitory gating evidenced by PPI (prepulse inhibition) deficits (Swedo et al., 1992; Breiter et al., 1996; Ziemann et al., 1997; Edgley and Lemon, 1999; Gilbert et al., 2004; Mantovani et al., 2006; Swerdlow and Sutherland, 2006; Ahmari et al., 2012; Bortolato and Pittenger, 2017). Transcranial magnetic stimulation confirms regional cortical disinhibition in both disorders (Ziemann et al., 1997; Gilbert et al., 2004; Mantovani et al., 2006), while elevated corticostriatal glutamatergic efflux was confirmed in OCD (Rosenberg et al., 2000). Similarly, both monkey and rat stereotaxic drug studies showed that disinhibiting sensorimotor corticostriatal glutamate (GLU) output was essential to generate tic-like symptoms, while inhibiting it was essential to diminish them (Pogorelov et al., 2015). These findings suggested that corticostriatal GLU can elicit, not just mediate, TS and OCD symptoms. CSTC loop hyperactivity in TS arises polygenically, most often from diffuse disruptions in synapse formation or function (Huang et al., 2017), but may etiologically arise in some TS cases as impairment either of inhibitory interneurons (Verkerk et al., 2003; Minzer et al., 2004; Penagarikano et al., 2011) or of inhibitory neurotransmission. Absence of histamine may disinhibit nigrostriatal, striatal, and cortical output in Hdc (histidine decarboxylase) gene deletion- associated hyperdopaminergic forms of human TS or mouse TS-like orofacial and sniffing stereotypies (Ercan-Sencicek et al., 2010; Karagiannidis et al., 2013; Castellan Baldan et al., 2014; Xu et al., 2015b). Diminished removal