Basal Ganglia Diseases; Tourette Syndrome; Learning; Molecular Biology; Neuroanatomy; Neurobiology; Neurophysiology; Neurosciences; Obsessive-Compulsive Disorder; Phobic Disorders; Psychopharmacology; Trichotillomania
My research is aimed towards a better understanding of a particular network of brain structures, called the basal ganglia, and the consequences of dysfunction of this network in various neuropsychiatric diseases. The basal ganglia are involved both in motor control and in the formation of habits. Abnormalities in this circuit are implicated in a variety of conditions characterized by maladaptive, inflexible behaviors - habits gone bad. These include obsessive-compulsive disorder, Tourette syndrome, and drug addiction.
Our research in the laboratory has two strands. First, we seek to better understand the mechanisms of normal basal ganglia-dependent habit-like learning, by manipulating this circuit in mice and then testing their ability to learn a variety of tasks. Second, we seek to better understand how perturbation of the basal ganglia system can lead to symptoms of psychiatric disease. We do this by recapitulating some of the biology of diseases such as Tourette syndrome, again in mice, and observing the behavioral and neurophysiological consequences.
I also direct the Yale OCD Research Clinic, where our research aims towards the better understanding of the biology of obsessive compulsive disorder and the development of new treatments. We have a number of active research programs. We are investigating abnormalities in the neurotransmitter glutamate in OCD and whehter glutamate modularing medications can be of therapeutic benefit. We are probling the network connectivity of the brain in OCD and Tourette syndrome using recent advances in fMRI imaging. We are exploring the phenomenological heterogeneity of OCD, seeking clues to how we might better personalize effective treatments. We are also developing innovative neurofeedback techniques, in which patients actually learn to control the activity of key brain regions, in an effort to develop a new type of nonpharmacological treatment.
Extensive Research Description
STUDIES OF BASAL GANGLIA FUNCTION IN MICE. The basal ganglia, consisting of the striatum (caudate-putamen) and related subcortical structures, have historically been considered to have primarily motor functions; but it has become increasingly clear that they are also involved in a variety of cognitive and affective processes. Disruption of normal basal ganglia function is seen in a variety of neuropsychiatric conditions, such as obsessive-compulsive disorder, Tourette syndrome, and drug addiction.
The striatum has been divided into distinct functional regions, though both the anatomical subdivisions and the functions with which they are associated remain approximate and subject to debate. The ventral striatum, consisting of the nucleus accumbens and related structures, has a well-documented role in reward and reward-driven learning, and has been extensively researched in the context of drug addiction. The dorsal striatum (caudate and putamen, in primates) is thought to have a role in the formation of motor and cognitive patterns and in forms of implicit learning, including the formation of habits.
The Pittenger laboratory is focused on better understanding the mechanisms of dorsal striatum-dependent habit-like learning, and of the consequences of its perturbation in various neuropsychiatric conditions. We conduct our researches primarily in mice, which allows us to take advantage of sophisticated reverse genetic techniques to perturb the striatal circuitry in molecularly precise ways and to target specific striatal subregions and neuronal subtypes.
DEVELOPMENT OF NOVEL BEHAVIORAL ASSAYS. A challenge in this line of work is that striatum-dependent learning processes have been less studied than those depending on other brain regions, such as hippocampus, cerebellum, and amygdala, and have barely been studied in mice at all prior to the last few years. A major thrust of our efforts has therefore been the establishment and validation of behavioral assays of striatal function in mice.
CREB IN STRIATAL SYNAPTIC PLASTICITY AND STRIATUM-DEPENDENT LEARNING. Dr. Pittenger’s initial work in this direction began during his Ph.D. studies with recent Nobel Prize winner Eric Kandel, with the production of transgenic mice expressing a dominant-negative mutatation of the ubiquitous transcription factor CREB, specifically in the striatum. CREB has long been known to have a conserved role in the establishment of long-lasting plasticity; for example, Dr. Pittenger’s earlier thesis work confirmed its role in the hippocampus in the stabilization of spatial learning (Pittenger et al, Neuron, 2002). However, the role of CREB-regulated processes in dorsal striatum-dependent habit-like learning had not previously been directly studied. We found that inhibition of CREB function in the dorsal striatum disrupts cortico-striatal synaptic plasticity and several striatum-dependent learning tasks (Pittenger et al, J Neurosci, 2006). This study represented the first time that the detailed mechanisms of striatum-dependent learning had been examined using genetic tools in mice. It also established a new paradigm (adapted from earlier work in rats) for the analysis of such learning processes in mice, laying the methodological groundwork for further analyses.
COMPETITIVE INTERACTIONS BETWEEN LEARNING SYSTEMS. More recent behavioral work in the Pittenger laboratory has examined the interaction of dorsal striatum-dependent learning with other types of learning and other circuits in the brain. We developed a novel cued water maze task for mice (again taking previous work in rats as our starting point), and found that the animals could learn to navigate using distinct strategies driven by either local or spatial cues. Lesions of the dorsal striatum disrupted cue-driven search, while lesions of the dorsal hippocampus disrupted spatial navigation. The remarkable finding came when we looked at interactions: hippocampal lesions not only left cued learning intact, they enhanced it. Conversely, striatal lesions not only left spatial learning unimpaired, they made it better. The same effect was see in our transgenic mice, in which striatal CREB is inhibited and corticostriatal plasticity is impaired: these animals have impaired cued learning but enhanced spatial learning (Lee et al, PNAS, 2008). This study was the first to document this sort of bi-directional enhancement after discrete brain lesions. We interpret the counter-intuitive results in terms of the multiple memory systems theory of learning. This theory posits that the mammalian brain contains several different learning systems, adapted for different types of environmental contingencies. For example, the hippocampus is adapted for the processing of spatial or relational information, while the dorsal striatum is hypothesized to be adapted for the gradual acquisition of discrete cue associations. Under normal circumstances they are activated in parallel; with training, whichever system is best able to master the relevant environmental contingency (e.g. to predict reward) comes to dominate. But in circumstances where two systems produce disparate behavioral outcomes they can destructively interfere with one another, or ‘compete’; this is particularly likely early in training, before differential reinforcement has led to the predominance of one system. We interpret the enhancement of the function subserved by one system after manipulations of the other as evidence for the alleviation of such competition.
STRIATAL SUBREGIONS. Our ongoing work in this direction seeks to refine our understanding of the structures underlying cued and spatial learning and their interaction. The dorsal striatum is not a homogeneous structure; different areas receive projections from functionally distinct regions of cortex and are therefore likely to process different sorts of information. In particular, the dorsolateral striatum (the putamen, in primates) receives projections from primary sensory and motor cortices, and therefore is likely to be involved in acquisition of cue-driven learning such as that we are seeing in the water maze task. The dorsomedial striatum, in contrast, receives input from association cortices and may have a more general role. Indeed, studies in rats suggest such a dissociation, and our own preliminary data suggest that restricted lesions of the dorsomedial striatum have very different effects from larger disruptions of the whole dorsal striatum.
We are addressing the question of functional dissociation within the dorsal striatum in several ways. First, we seek to better define what is meant by the ‘dorsomedial striatum’ and ‘dorsolateral striatum’ in this context by examining striatal activation by water maze learning in an unbiased way; we have found the different tasks to produce distinct patterns of striatal activation, enen though they share all sensory, motor, and motivational characteristics. Second, we are targeting lesions to putative striatal subregions and examining the behavioral consequences. Finally, we are targeting disruptions of CREB-mediated transcription to striatal subregions using recombinant adeno-associated viruses (rAAV), to see whether disruption in a restricted subregion is sufficient to recapitulate the effects we see when CREB is inhibited throughout the dorsal striatum in our transgenic mice.
NEW METHODOLOGIES FOR PROBING AND PERTURBING STRIATAL FUNCTION. This latter project highlights another theme in the Pittenger laboratory’s research portfolio, the development of novel tools for precise manipulation of specific mechanisms and cell populations in the dorsal striatum, and in other neural circuits. The production of transgenic mice allowed restriction of a molecular manipulation to the dorsal striatum, but it does not suffice for more specific targeting of manipulations to discrete subregions. For that purpose we are now using engineered rAAV vectors to deliver our CREB dominant negative construct, and other gene products, into defined brain areas by stereotaxic surgery. A first-generation vector, which we are currently using, allows expression of a CREB dominant negative in target brain regions of varying size. A second-generation vector, which is under development and working well in vitro, permits the temporal regulation of the delivered gene, such that it can be turned on and off; this will allow behavioral experimental designs not possible with static manipulations, such as dissociating learning from recall.
Another major effort in the laboratory is the targeting of defined striatal cell populations. The striatum, like any other brain region or structure, is not homogenous; it is made up of distinct populations of principal cells and a number of different classes of interneurons. Different cell types are likely to make different contributions to striatal function, and perturbation of one or another cell type may result in discrete behavioral abnormalities or (in humans) patterns of psychopathology. We have developed a method, combining recombinant viruses with transgenic technologies, to perturb defined cell populations, without disrupting similar cells elsewhere in the brain or neighboring cells of different types.
MODELING PSYCHIATRIC DISEASE. We are applying this technology to model neuropsychiatric conditions affecting the striatum, especially Tourette syndrome. This represents a third focus of the laboratory. Modeling psychiatric disease in animals has proven enormously challenging, because etiology is often obscure and symptomatology is often difficult to translate to non-verbal species. We believe that the development of valid models hinges on a sufficient degree of understanding of pathophysiology to ensure validity when translating to animals.
Fortunately, studies at Yale and elsewhere are beginning to produce such understanding in the case of Tourette syndrome. We are using genetic methods to produce putative models of Tourette syndrome based both on post-mortem findings (in collaboration with Flora Vaccarino) and on genetic insights (in collaboration with Matt State). These animals are then being tested in a variety of behavioral assays to assess their recapitulation of Tourette syndrome phenomenology, explore secondary and tertiary consequences of the initial manipulations, and investigate the response to both established and novel medications.
A FOCUS ON TRANSLATIONAL RESEARCH: NEW MEDICATIONS FOR OBSESSIVE-COMPULSIVE DISORDER (OCD). The final focus of the Pittenger laboratory is also translational. Dr. Pittenger is Director of the Yale OCD Research Clinic, where he has found glutamate-modulating medications to be of potential benefit in the treatment of patients with obsessive-compulsive disorder (a condition in which basal ganglia dysfunction is implicated). We are examining the behavioral and molecular effects of such glutamate-modulating drugs in animals, to better understand their role in patients with this and related conditions. As new animal models of disorders of the basal ganglia, like OCD, become available, we hope to use this translational approach to advance our understanding both of the normal role of the basal ganglia in behavior and its perturbation in disease, and to develop new generations of therapeutics for the psychiatric population.
- Striatal subregions in cued-driven navigation, instrumental habit, and other behaviors
- Developing new techniques for the targeted disruption of striatal interneurons
- Modeling Tourette syndrome in mice: genetic and neuropathological approaches
- Histidine decarboxylase knockout mice, an animal model of a rare genetic form of Tourette syndrome
- Histamine modulation of basal ganglia information processing
- Microglial abnormalities in animal models of Toruette syndrome
- Glutamate dysregulation in OCD: an MRS Study
- Functional and structural connectomics in OCD and Tourette syndrome
- Neurofeedback targeting the orbitofrontal cortex for the treatment of OCD
- Biological and phenomenological predictors of treatment response in OCD
- The genetics of OCD
- Xu, M., Kobets, A., Du, J.C., Lennington, J., Li, L., Banasr, M., Duman, R.S., Vaccarino, F.M., DiLeone, R.J., and Pittenger, C. (2015). Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proceedings of the National Academy of Sciences, USA, 112:893-8.
- Calstellan Baldan, L., Williams, K.A., Gallezot, J.-D., Pogorelov, V., Rapanelli, M., Crowley, M., Anderson, G.M., Loring, E., Gorczyca, R., Billingslea, E., Wasylink, s., Panza, K.E., Ercan-Sencicek, A.G., Krusong, K., Leventhal, B.L., Ohtsu, H., Bloch, M. H., Hughes, Z. A., Krystal, J. H., Mayes, L., de Araujo, I., Ding, Y. S., State, M. W., & Pittenger, C. Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. Neuron, 81:77-90.
- Anticevic, A., Hu, S., Zhang, S., Savic, A., Billingslea, E., Wasylink, S., Repovs, G., Cole, M.W., Bednarski, S., Krystal, J.H., Bloch, M.H., Li, C.S., and Pittenger, C. (2014). Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder. Biological Psychiatry, 75:595-605.
- Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Bloch, M.H., Wasylink, S., Landeros-Weisenberger, A., Panza, K.E., Billingslea, E., Leckman, J.F., Krystal, J.H., Bhagwagar, Z., Sanacora, G., and Pittenger C. (2012).Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012 Dec 1;72(11):964-70
- Pittenger, C., Bloch, M.H., and Williams, K. (2011). Glutamate abnormalities in obsessive-compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacology and Therapeutics 132:314-32.
- Lee, A.S., Duman, R.S., and Pittenger, C. (2008). A double dissociation revealing bidirectional competition between striatum and hippocampus during learning. Proceedings of the National Academy of Sciences, USA, 105:17163-8.