Toward a Neural Model of TS+OCD

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Minnesota
Investigators Name
Burton, Frank, PhD

Regardless of their actual origin, most genetic, organic, or autoimmune neurobiological disorders with behavioral aspects, are probably mediated through specific hyperactivated or deactivated neuronal circuits. Yet for most behavioral disorders little is known about their circuitry, or neuronal bases. One disorder where it is important to precisely understand the responsible neural circuitry is comorbid TS+OCD (Tourette Syndrome plus Obsessive-Compulsive Disorder). Our lab is addressing the goal of understanding the neuronal basis of TS+OCD, with a genetic tool we devised for specific, chronic neuropotentiation of predetermined brain circuits—in essence, a tool for precise circuit-testing of behavior. Using our “neuropotentiating transgene,” we have asked whether we can reproduce in mice the complex tic+compulsion symptoms and therapeutic drug responses of TS+OCD, simply by chronically hyper-activating particular subtypes of neurons in some of the same brain regions that “light up” in PET scans of people with TS+OCD. Recently we have engineered transgenic mice to express our neuropotentiating transgene specifically within a small cortical-limbic subset of neurons suspected of being hyperactive or affected in TS and OCD. These are the cortical-limbic dopamine D1- and serotonin 5-HT2a,c-receptor expressing (D1/5-HT2a,c+) neurons that glutamatergically excite orbitofrontal, somatosensory, limbic and efferent striatal circuits. These mice exhibit all the comorbid symptoms and drug responses of people with both TS+OCD, and they include: OCD-like generalized behavioral repetition and OCD/trichotillomania-like behaviors; TS-like juvenile-onset tics, including increased tic incidence, tic complexity and tic severity in males (suggesting that sex hormones, not genes or autoimmune differences, are the culprit aggravating tics in males or suppressing them in females); voluntary tic suppression; tic responsiveness to different pharmacological classes of human TS+OCD drug therapies including haldol, clonidine, and bromocriptine; and symptom aggravation by anxiety-inducing drugs and symptom amelioration by anxiety-reducing drugs. Moreover, the mice respond to other cortical-, limbic-, and striatal-acting drugs in a fashion consistent with a precise neuronal circuit model of TS+OCD symptoms, i.e. the “Cortical-limbic Glutamatergic Neuron” (CGN) model. Our CGN model of TS+OCD predicts that tics, primary compulsions, and obsessions (or “thought compulsions”) are all triggered by hyperactivity of various cortical-limbic projection neurons’ glutamatergic excitation of the striatum. This excitation then elicits associated or compensatory striatal changes – including elevated striatal glutamate, compensatory elevation of inhibitory striatal dopamine D2 receptors, and reduced striatal responsiveness to cortical-limbic excitatory input. Since the development and publication of our Cortical-limbic Glutamatergic Neuron model of TS+OCD, each of its predicted efferent striatal consequences has been confirmed by human MRS, PET, or fMRI neuroimaging studies, including increased striatal glutamate in OCD; increased striatal D2 receptors in TS; and decreased striatal responsiveness in TS. These data support the symptom- and drug response-predictive capability of this transgenic model of tics+compulsions, and validates the accuracy of the Cortical-limbic Glutamatergic Neuron model of TS+OCD. Our current studies are focusing on testing this model in two ways. First, we plan to directly test these “ticcy-compulsive” mice for TS+OCDlike increases in cortical-limbic glucose metabolism and glutamate release, and increased striatal D2 receptors. Second, we plan to use the TS+OCD-like mice to pre-clinically screen new, anti-glutamatergic drug therapies, which we hope will provide more effective (with fewer side effects) pharmacotherapy for TS, OCD and OCD related compulsive disorders such as trichotillomania. Readers may be interested in seeing a local press report on the mice: facprof/startrib.html: For more about Burton Lab web sites: www. Frank H. Burton, Ph.D. University of Minnesota Minneapolis, MN Award: $66,099 Tourette Association of America Inc. – Research Grant Award 2001-2002