Basal Ganglia Diseases; Tourette Syndrome; Learning; Molecular Biology; Neuroanatomy; Neurobiology; Neurophysiology; Neurosciences; Obsessive-Compulsive Disorder; Phobic Disorders; Psychopharmacology; Trichotillomania
Psychiatry: Clinical Neuroscience Research Unit | Connecticut Mental Health Center | Neurocognition, Neurocomputation, and Neurogenetics, Division of | Neuroscience Research Training Program (NRTP) | Obsessive Compulsive Disorder Research Clinic | PittLab
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
Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.
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.
- Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. 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.
Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder.
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
Glutamate abnormalities in obsessive-compulsive disorder: neurobiology, pathophysiology, and treatment.
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.
A double dissociation revealing bidirectional competition between striatum and hippocampus during learning.
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.
Full List of PubMed Publications
- Xu J, Hartley BJ, Kurup P, Phillips A, Topol A, Xu M, Ononenyi C, Foscue E, Ho SM, Baguley TD, Carty N, Barros CS, Müller U, Gupta S, Gochman P, Rapoport J, Ellman JA, Pittenger C, Aronow B, Nairn AC, Nestor MW, Lombroso PJ, Brennand KJ: Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Mol Psychiatry. 2016 Oct 18; 2016 Oct 18. PMID: 27752082
- Frick L, Rapanelli M, Abbasi E, Ohtsu H, Pittenger C: Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation. Brain Behav Immun. 2016 Oct; 2016 Jul 2. PMID: 27381299
- Rapanelli M, Frick LR, Horn KD, Schwarcz RC, Pogorelov V, Nairn AC, Pittenger C: The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. J Biol Chem. 2016 Sep 30; 2016 Aug 10. PMID: 27510032
- Boedhoe PS, Schmaal L, Abe Y, Ameis SH, Arnold PD, Batistuzzo MC, Benedetti F, Beucke JC, Bollettini I, Bose A, Brem S, Calvo A, Cheng Y, Cho KI, Dallaspezia S, Denys D, Fitzgerald KD, Fouche JP, Giménez M, Gruner P, Hanna GL, Hibar DP, Hoexter MQ, Hu H, Huyser C, Ikari K, Jahanshad N, Kathmann N, Kaufmann C, Koch K, Kwon JS, Lazaro L, Liu Y, Lochner C, Marsh R, Martínez-Zalacaín I, Mataix-Cols D, Menchón JM, Minuzzi L, Nakamae T, Nakao T, Narayanaswamy JC, Piras F, Piras F, Pittenger C, Reddy YC, Sato JR, Simpson HB, Soreni N, Soriano-Mas C, Spalletta G, Stevens MC, Szeszko PR, Tolin DF, Venkatasubramanian G, Walitza S, Wang Z, van Wingen GA, Xu J, Xu X, Yun JY, Zhao Q, ENIGMA OCD Working Group., Thompson PM, Stein DJ, van den Heuvel OA: Distinct Subcortical Volume Alterations in Pediatric and Adult OCD: A Worldwide Meta- and Mega-Analysis. Am J Psychiatry. 2016 Sep 9; 2016 Sep 9. PMID: 27609241
- Gruner P, Pittenger C: Cognitive inflexibility in Obsessive-Compulsive Disorder. Neuroscience. 2016 Aug 1; 2016 Aug 1. PMID: 27491478
- Rapanelli M, Pittenger C: Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions. Neuropharmacology. 2016 Jul; 2015 Aug 14. PMID: 26282120
- Xu M, Li L, Pittenger C: Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming. Neuroscience. 2016 Jun 2; 2016 Mar 8. PMID: 26968763
- Pittenger C, Adams TG Jr, Gallezot JD, Crowley MJ, Nabulsi N, James Ropchan, Gao H, Kichuk SA, Simpson R, Billingslea E, Hannestad J, Bloch M, Mayes L, Bhagwagar Z, Carson RE: OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding. J Affect Disord. 2016 May 15; 2016 Feb 9. PMID: 26919057
- Issaria Y, Jakubovski E, Bartley CA, Pittenger C, Bloch MH: Early onset of response with selective serotonin reuptake inhibitors in obsessive-compulsive disorder: a meta-analysis. J Clin Psychiatry. 2016 May. PMID: 27249090
- Radua J, Stoica T, Scheinost D, Pittenger C, Hampson M: Neural correlates of success and failure signals during neurofeedback learning. Neuroscience. 2016 Apr 5; 2016 Apr 5. PMID: 27063101
- Kelmendi B, Adams T Jr, Jakubovski E, Hawkins KA, Coric V, Pittenger C: Probing Implicit Learning in Obsessive-Compulsive Disorder: Moderating Role of Medication on the Weather Prediction Task. J Obsessive Compuls Relat Disord. 2016 Apr. PMID: 27134820
- Gruner P, Anticevic A, Lee D, Pittenger C: Arbitration between Action Strategies in Obsessive-Compulsive Disorder. Neuroscientist. 2016 Apr; 2015 Jan 20. PMID: 25605642
- Van Schalkwyk GI, Bhalla IP, Griepp M, Kelmendi B, Davidson L, Pittenger C: Toward understanding the heterogeneity in obsessive-compulsive disorder: Evidence from narratives in adult patients. Aust N Z J Psychiatry. 2016 Jan; 2015 Apr 8. PMID: 25855685
- Frick L, Pittenger C: Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS. J Immunol Res. 2016; 2016 Dec 7. PMID: 28053994
- Pushkarskaya H, Tolin D, Ruderman L, Kirshenbaum A, Kelly JM, Pittenger C, Levy I: Decision-making under uncertainty in obsessive-compulsive disorder. J Psychiatr Res. 2015 Oct; 2015 Aug 12. PMID: 26343609
- Pittenger C: Glutamatergic agents for OCD and related disorders. Curr Treat Options Psychiatry. 2015 Sep. PMID: 26301176
- Pittenger C, Bloch MH, Wasylink S, Billingslea E, Simpson R, Jakubovski E, Kelmendi B, Sanacora G, Coric V: Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a pilot randomized placebo-controlled trial. J Clin Psychiatry. 2015 Aug. PMID: 26214725
- Pittenger C: Glutamate modulators in the treatment of obsessive-compulsive disorder. Psychiatr Ann. 2015 Jun. PMID: 26236057
- Xu M, Li L, Ohtsu H, Pittenger C: Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear. Neurosci Lett. 2015 May 19; 2015 Apr 1. PMID: 25841792
- Pogorelov V, Xu M, Smith HR, Buchanan GF, Pittenger C: Corticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition. Exp Neurol. 2015 Mar; 2015 Jan 15. PMID: 25597650
- Xu M, Kobets A, Du JC, Lennington J, Li L, Banasr M, Duman RS, Vaccarino FM, DiLeone RJ, Pittenger C: Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A. 2015 Jan 20; 2015 Jan 5. PMID: 25561540
- Yu D, Mathews CA, Scharf JM, Neale BM, Davis LK, Gamazon ER, Derks EM, Evans P, Edlund CK, Crane J, Fagerness JA, Osiecki L, Gallagher P, Gerber G, Haddad S, Illmann C, McGrath LM, Mayerfeld C, Arepalli S, Barlassina C, Barr CL, Bellodi L, Benarroch F, Berrió GB, Bienvenu OJ, Black DW, Bloch MH, Brentani H, Bruun RD, Budman CL, Camarena B, Campbell DD, Cappi C, Silgado JC, Cavallini MC, Chavira DA, Chouinard S, Cook EH, Cookson MR, Coric V, Cullen B, Cusi D, Delorme R, Denys D, Dion Y, Eapen V, Egberts K, Falkai P, Fernandez T, Fournier E, Garrido H, Geller D, Gilbert DL, Girard SL, Grabe HJ, Grados MA, Greenberg BD, Gross-Tsur V, Grünblatt E, Hardy J, Heiman GA, Hemmings SM, Herrera LD, Hezel DM, Hoekstra PJ, Jankovic J, Kennedy JL, King RA, Konkashbaev AI, Kremeyer B, Kurlan R, Lanzagorta N, Leboyer M, Leckman JF, Lennertz L, Liu C, Lochner C, Lowe TL, Lupoli S, Macciardi F, Maier W, Manunta P, Marconi M, McCracken JT, Mesa Restrepo SC, Moessner R, Moorjani P, Morgan J, Muller H, Murphy DL, Naarden AL, Nurmi E, Ochoa WC, Ophoff RA, Pakstis AJ, Pato MT, Pato CN, Piacentini J, Pittenger C, Pollak Y, Rauch SL, Renner T, Reus VI, Richter MA, Riddle MA, Robertson MM, Romero R, Rosário MC, Rosenberg D, Ruhrmann S, Sabatti C, Salvi E, Sampaio AS, Samuels J, Sandor P, Service SK, Sheppard B, Singer HS, Smit JH, Stein DJ, Strengman E, Tischfield JA, Turiel M, Valencia Duarte AV, Vallada H, Veenstra-VanderWeele J, Walitza S, Wang Y, Weale M, Weiss R, Wendland JR, Westenberg HG, Shugart YY, Hounie AG, Miguel EC, Nicolini H, Wagner M, Ruiz-Linares A, Cath DC, McMahon W, Posthuma D, Oostra BA, Nestadt G, Rouleau GA, Purcell S, Jenike MA, Heutink P, Hanna GL, Conti DV, Arnold PD, Freimer NB, Stewart SE, Knowles JA, Cox NJ, Pauls DL: Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD. Am J Psychiatry. 2015 Jan; 2014 Oct 31. PMID: 25158072
- Fernandez TV, King RA, Pittenger C: Tourette's syndrome and translational clinical science. J Am Acad Child Adolesc Psychiatry. 2015 Jan. PMID: 25524784
- Rapanelli M, Frick LR, Pogorelov V, Ota KT, Abbasi E, Ohtsu H, Pittenger C: Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome. Eur Neuropsychopharmacol. 2014 Dec; 2014 Nov 4. PMID: 25464894
- Scheinost D, Stoica T, Wasylink S, Gruner P, Saksa J, Pittenger C, Hampson M: Resting state functional connectivity predicts neurofeedback response. Front Behav Neurosci. 2014 Sep 24; 2014 Sep 24. PMID: 25309375
- Bloch MH, Bartley CA, Zipperer L, Jakubovski E, Landeros-Weisenberger A, Pittenger C, Leckman JF: Meta-analysis: hoarding symptoms associated with poor treatment outcome in obsessive-compulsive disorder. Mol Psychiatry. 2014 Sep; 2014 Jun 10. PMID: 24912494
- Pittenger C, Bloch MH: Pharmacological treatment of obsessive-compulsive disorder. Psychiatr Clin North Am. 2014 Sep; 2014 Jul 24. PMID: 25150568
- McGrath LM, Yu D, Marshall C, Davis LK, Thiruvahindrapuram B, Li B, Cappi C, Gerber G, Wolf A, Schroeder FA, Osiecki L, O'Dushlaine C, Kirby A, Illmann C, Haddad S, Gallagher P, Fagerness JA, Barr CL, Bellodi L, Benarroch F, Bienvenu OJ, Black DW, Bloch MH, Bruun RD, Budman CL, Camarena B, Cath DC, Cavallini MC, Chouinard S, Coric V, Cullen B, Delorme R, Denys D, Derks EM, Dion Y, Rosário MC, Eapen V, Evans P, Falkai P, Fernandez TV, Garrido H, Geller D, Grabe HJ, Grados MA, Greenberg BD, Gross-Tsur V, Grünblatt E, Heiman GA, Hemmings SM, Herrera LD, Hounie AG, Jankovic J, Kennedy JL, King RA, Kurlan R, Lanzagorta N, Leboyer M, Leckman JF, Lennertz L, Lochner C, Lowe TL, Lyon GJ, Macciardi F, Maier W, McCracken JT, McMahon W, Murphy DL, Naarden AL, Neale BM, Nurmi E, Pakstis AJ, Pato MT, Pato CN, Piacentini J, Pittenger C, Pollak Y, Reus VI, Richter MA, Riddle M, Robertson MM, Rosenberg D, Rouleau GA, Ruhrmann S, Sampaio AS, Samuels J, Sandor P, Sheppard B, Singer HS, Smit JH, Stein DJ, Tischfield JA, Vallada H, Veenstra-VanderWeele J, Walitza S, Wang Y, Wendland JR, Shugart YY, Miguel EC, Nicolini H, Oostra BA, Moessner R, Wagner M, Ruiz-Linares A, Heutink P, Nestadt G, Freimer N, Petryshen T, Posthuma D, Jenike MA, Cox NJ, Hanna GL, Brentani H, Scherer SW, Arnold PD, Stewart SE, Mathews CA, Knowles JA, Cook EH, Pauls DL, Wang K, Scharf JM: Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study. J Am Acad Child Adolesc Psychiatry. 2014 Aug; 2014 Jun 24. PMID: 25062598
- Yang GJ, Murray JD, Repovs G, Cole MW, Savic A, Glasser MF, Pittenger C, Krystal JH, Wang XJ, Pearlson GD, Glahn DC, Anticevic A: Altered global brain signal in schizophrenia. Proc Natl Acad Sci U S A. 2014 May 20; 2014 May 5. PMID: 24799682
- Anticevic A, Hu S, Zhang S, Savic A, Billingslea E, Wasylink S, Repovs G, Cole MW, Bednarski S, Krystal JH, Bloch MH, Li CS, Pittenger C: Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder. Biol Psychiatry. 2014 Apr 15; 2013 Nov 4. PMID: 24314349
- Lee AS, André JM, Pittenger C: Lesions of the dorsomedial striatum delay spatial learning and render cue-based navigation inflexible in a water maze task in mice. Front Behav Neurosci. 2014 Feb 13; 2014 Feb 13. PMID: 24592223
- Castellan Baldan L, Williams KA, Gallezot JD, Pogorelov V, Rapanelli M, Crowley M, Anderson GM, Loring E, Gorczyca R, Billingslea E, Wasylink S, Panza KE, Ercan-Sencicek AG, Krusong K, Leventhal BL, Ohtsu H, Bloch MH, Hughes ZA, Krystal JH, Mayes L, de Araujo I, Ding YS, State MW, Pittenger C: Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. Neuron. 2014 Jan 8. PMID: 24411733
- Pittenger C: Disorders of memory and plasticity in psychiatric disease. Dialogues Clin Neurosci. 2013 Dec. PMID: 24459412
- Davis LK, Yu D, Keenan CL, Gamazon ER, Konkashbaev AI, Derks EM, Neale BM, Yang J, Lee SH, Evans P, Barr CL, Bellodi L, Benarroch F, Berrio GB, Bienvenu OJ, Bloch MH, Blom RM, Bruun RD, Budman CL, Camarena B, Campbell D, Cappi C, Cardona Silgado JC, Cath DC, Cavallini MC, Chavira DA, Chouinard S, Conti DV, Cook EH, Coric V, Cullen BA, Deforce D, Delorme R, Dion Y, Edlund CK, Egberts K, Falkai P, Fernandez TV, Gallagher PJ, Garrido H, Geller D, Girard SL, Grabe HJ, Grados MA, Greenberg BD, Gross-Tsur V, Haddad S, Heiman GA, Hemmings SM, Hounie AG, Illmann C, Jankovic J, Jenike MA, Kennedy JL, King RA, Kremeyer B, Kurlan R, Lanzagorta N, Leboyer M, Leckman JF, Lennertz L, Liu C, Lochner C, Lowe TL, Macciardi F, McCracken JT, McGrath LM, Mesa Restrepo SC, Moessner R, Morgan J, Muller H, Murphy DL, Naarden AL, Ochoa WC, Ophoff RA, Osiecki L, Pakstis AJ, Pato MT, Pato CN, Piacentini J, Pittenger C, Pollak Y, Rauch SL, Renner TJ, Reus VI, Richter MA, Riddle MA, Robertson MM, Romero R, Rosàrio MC, Rosenberg D, Rouleau GA, Ruhrmann S, Ruiz-Linares A, Sampaio AS, Samuels J, Sandor P, Sheppard B, Singer HS, Smit JH, Stein DJ, Strengman E, Tischfield JA, Valencia Duarte AV, Vallada H, Van Nieuwerburgh F, Veenstra-Vanderweele J, Walitza S, Wang Y, Wendland JR, Westenberg HG, Shugart YY, Miguel EC, McMahon W, Wagner M, Nicolini H, Posthuma D, Hanna GL, Heutink P, Denys D, Arnold PD, Oostra BA, Nestadt G, Freimer NB, Pauls DL, Wray NR, Stewart SE, Mathews CA, Knowles JA, Cox NJ, Scharf JM: Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet. 2013 Oct; 2013 Oct 24. PMID: 24204291
- Bloch MH, Green C, Kichuk SA, Dombrowski PA, Wasylink S, Billingslea E, Landeros-Weisenberger A, Kelmendi B, Goodman WK, Leckman JF, Coric V, Pittenger C: Long-term outcome in adults with obsessive-compulsive disorder. Depress Anxiety. 2013 Aug; 2013 Mar 26. PMID: 23532944
- Niciu MJ, Grunschel BD, Corlett PR, Pittenger C, Bloch MH: Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after ketamine infusion in patients with obsessive-compulsive disorder and a history of major depressive disorder. J Psychopharmacol. 2013 Jul; 2013 May 15. PMID: 23676198
- Stewart SE, Yu D, Scharf JM, Neale BM, Fagerness JA, Mathews CA, Arnold PD, Evans PD, Gamazon ER, Davis LK, Osiecki L, McGrath L, Haddad S, Crane J, Hezel D, Illman C, Mayerfeld C, Konkashbaev A, Liu C, Pluzhnikov A, Tikhomirov A, Edlund CK, Rauch SL, Moessner R, Falkai P, Maier W, Ruhrmann S, Grabe HJ, Lennertz L, Wagner M, Bellodi L, Cavallini MC, Richter MA, Cook EH Jr, Kennedy JL, Rosenberg D, Stein DJ, Hemmings SM, Lochner C, Azzam A, Chavira DA, Fournier E, Garrido H, Sheppard B, Umaña P, Murphy DL, Wendland JR, Veenstra-VanderWeele J, Denys D, Blom R, Deforce D, Van Nieuwerburgh F, Westenberg HG, Walitza S, Egberts K, Renner T, Miguel EC, Cappi C, Hounie AG, Conceição do Rosário M, Sampaio AS, Vallada H, Nicolini H, Lanzagorta N, Camarena B, Delorme R, Leboyer M, Pato CN, Pato MT, Voyiaziakis E, Heutink P, Cath DC, Posthuma D, Smit JH, Samuels J, Bienvenu OJ, Cullen B, Fyer AJ, Grados MA, Greenberg BD, McCracken JT, Riddle MA, Wang Y, Coric V, Leckman JF, Bloch M, Pittenger C, Eapen V, Black DW, Ophoff RA, Strengman E, Cusi D, Turiel M, Frau F, Macciardi F, Gibbs JR, Cookson MR, Singleton A, North American Brain Expression Consortium., Hardy J, UK Brain Expression Database., Crenshaw AT, Parkin MA, Mirel DB, Conti DV, Purcell S, Nestadt G, Hanna GL, Jenike MA, Knowles JA, Cox N, Pauls DL: Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry. 2013 Jul; 2012 Aug 14. PMID: 22889921
- Kichuk SA, Torres AR, Fontenelle LF, Rosário MC, Shavitt RG, Miguel EC, Pittenger C, Bloch MH: Symptom dimensions are associated with age of onset and clinical course of obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jul 1; 2013 Feb 12. PMID: 23410525
- Scheinost D, Stoica T, Saksa J, Papademetris X, Constable RT, Pittenger C, Hampson M: Orbitofrontal cortex neurofeedback produces lasting changes in contamination anxiety and resting-state connectivity. Transl Psychiatry. 2013 Apr 30; 2013 Apr 30. PMID: 23632454
- Quinn JJ, Pittenger C, Lee AS, Pierson JL, Taylor JR: Striatum-dependent habits are insensitive to both increases and decreases in reinforcer value in mice. Eur J Neurosci. 2013 Mar; 2013 Jan 9. PMID: 23298231
- Panza KE, Pittenger C, Bloch MH: Age and gender correlates of pulling in pediatric trichotillomania. J Am Acad Child Adolesc Psychiatry. 2013 Mar. PMID: 23452681
- Bloch MH, Panza KE, Grant JE, Pittenger C, Leckman JF: N-Acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. J Am Acad Child Adolesc Psychiatry. 2013 Mar. PMID: 23452680
- Frick LR, Williams K, Pittenger C: Microglial dysregulation in psychiatric disease. Clin Dev Immunol. 2013; 2013 Apr 18. PMID: 23690824
- Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, Pittenger C: Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012 Dec 1; 2012 Jul 10. PMID: 22784486
- Middei S, Spalloni A, Longone P, Pittenger C, O'Mara SM, Marie H, Ammassari-Teule M: CREB selectively controls learning-induced structural remodeling of neurons. Learn Mem. 2012 Jul 18; 2012 Jul 18. PMID: 22815537
- Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ: The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Transl Psychiatry. 2012 Jul 10; 2012 Jul 10. PMID: 22781170
- Hampson M, Stoica T, Saksa J, Scheinost D, Qiu M, Bhawnani J, Pittenger C, Papademetris X, Constable T: Real-time fMRI biofeedback targeting the orbitofrontal cortex for contamination anxiety. J Vis Exp. 2012 Jan 20; 2012 Jan 20. PMID: 22297729
- Pittenger C: Pathophysiological modeling of obsessive-compulsive disorder: challenges, and progress. Biol Psychiatry. 2011 Dec 1. PMID: 22045035
- Pittenger C, Bloch MH, Williams K: Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011 Dec; 2011 Sep 22. PMID: 21963369
- Jakubovski E, Pittenger C, Torres AR, Fontenelle LF, do Rosario MC, Ferrão YA, de Mathis MA, Miguel EC, Bloch MH: Dimensional correlates of poor insight in obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15; 2011 May 27. PMID: 21640153
- Kelmendi B, Holsbach-Beltrame M, McIntosh AM, Hilt L, George ED, Kitchen RR, Carlyle BC, Pittenger C, Coric V, Nolen-Hoeksema S, Sanacora G, Simen AA: Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder. Neurosci Lett. 2011 Jun 8; 2011 Apr 20. PMID: 21529705
- Pittenger C: Epigenetic modification of the BDNF locus by early-life enrichment: towards a molecular correlate of resilience? Neurosci Lett. 2011 May 20; 2011 Mar 22. PMID: 21435373
- Krusong K, Ercan-Sencicek AG, Xu M, Ohtsu H, Anderson GM, State MW, Pittenger C: High levels of histidine decarboxylase in the striatum of mice and rats. Neurosci Lett. 2011 May 16; 2011 Apr 1. PMID: 21440039
- Baldan Ramsey LC, Xu M, Wood N, Pittenger C: Lesions of the dorsomedial striatum disrupt prepulse inhibition. Neuroscience. 2011 Apr 28; 2011 Feb 15. PMID: 21315809
- Bloch M, State M, Pittenger C: Recent advances in Tourette syndrome. Curr Opin Neurol. 2011 Apr. PMID: 21386676
- Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ: Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A. 2010 Nov 2; 2010 Oct 18. PMID: 20956308
- Gourley SL, Lee AS, Howell JL, Pittenger C, Taylor JR: Dissociable regulation of instrumental action within mouse prefrontal cortex. Eur J Neurosci. 2010 Nov; 2010 Oct 12. PMID: 21044173
- Baldan Ramsey LC, Pittenger C: Cued and spatial learning in the water maze: equivalent learning in male and female mice. Neurosci Lett. 2010 Oct 11; 2010 Aug 5. PMID: 20691760
- Bloch MH, McGuire J, Landeros-Weisenberger A, Leckman JF, Pittenger C: Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder. Mol Psychiatry. 2010 Aug; 2009 May 26. PMID: 19468281
- Bloch MH, Pittenger C: The Genetics of Obsessive-Compulsive Disorder. Curr Psychiatry Rev. 2010 May 1. PMID: 23970845
- Landeros-Weisenberger A, Bloch MH, Kelmendi B, Wegner R, Nudel J, Dombrowski P, Pittenger C, Krystal JH, Goodman WK, Leckman JF, Coric V: Dimensional predictors of response to SRI pharmacotherapy in obsessive-compulsive disorder. J Affect Disord. 2010 Feb; 2009 Jul 3. PMID: 19577308
- Fasano S, Pittenger C, Brambilla R: Inhibition of CREB activity in the dorsal portion of the striatum potentiates behavioral responses to drugs of abuse. Front Behav Neurosci. 2009 Sep 9; 2009 Sep 9. PMID: 19826621
- Bloch MH, Landeros-Weisenberger A, Rosario MC, Pittenger C, Leckman JF: Meta-analysis of the symptom structure of obsessive-compulsive disorder. Am J Psychiatry. 2008 Dec; 2008 Oct 15. PMID: 18923068
- Lee AS, Duman RS, Pittenger C: A double dissociation revealing bidirectional competition between striatum and hippocampus during learning. Proc Natl Acad Sci U S A. 2008 Nov 4; 2008 Oct 27. PMID: 18955704
- Bloch MH, Landeros-Weisenberger A, Sen S, Dombrowski P, Kelmendi B, Coric V, Pittenger C, Leckman JF: Association of the serotonin transporter polymorphism and obsessive-compulsive disorder: systematic review. Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5. PMID: 18186076
- Pittenger C, Kelmendi B, Wasylink S, Bloch MH, Coric V: Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a series of 13 cases, with long-term follow-up. J Clin Psychopharmacol. 2008 Jun. PMID: 18480706
- Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA: Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med. 2008 Jun; 2008 Jun 1. PMID: 18516051
- Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G: Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008. PMID: 18698875
- Pittenger C, Duman RS: Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology. 2008 Jan; 2007 Sep 12. PMID: 17851537
- Bloch MH, Landeros-Weisenberger A, Dombrowski P, Kelmendi B, Wegner R, Nudel J, Pittenger C, Leckman JF, Coric V: Systematic review: pharmacological and behavioral treatment for trichotillomania. Biol Psychiatry. 2007 Oct 15; 2007 Aug 28. PMID: 17727824
- Pittenger C, Sanacora G, Krystal JH: The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol Disord Drug Targets. 2007 Apr. PMID: 17430148
- Pittenger C, Desan PH: Gabapentin abuse, and delirium tremens upon gabapentin withdrawal. J Clin Psychiatry. 2007 Mar. PMID: 17388722
- Coric V, Kelmendi B, Pittenger C, Wasylink S, Bloch MH, Green J: Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with trichotillomania. J Clin Psychiatry. 2007 Jan. PMID: 17284151
- Sasso DA, Kalanithi PS, Trueblood KV, Pittenger C, Kelmendi B, Wayslink S, Malison RT, Krystal JH, Coric V: Beneficial effects of the glutamate-modulating agent riluzole on disordered eating and pathological skin-picking behaviors. J Clin Psychopharmacol. 2006 Dec. PMID: 17110840
- Pittenger C, Naungayan C, Kendell SF, Coric V, Malison R, Krystal JH, Sanacora GS: Visual hallucinations from the addition of riluzole to memantine and bupropion. J Clin Psychopharmacol. 2006 Apr. PMID: 16633160
- Pittenger C, Fasano S, Mazzocchi-Jones D, Dunnett SB, Kandel ER, Brambilla R: Impaired bidirectional synaptic plasticity and procedural memory formation in striatum-specific cAMP response element-binding protein-deficient mice. J Neurosci. 2006 Mar 8. PMID: 16525060
- Pittenger C, Krystal JH, Coric V: Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder. NeuroRx. 2006 Jan. PMID: 16490414
- Lafleur DL, Pittenger C, Kelmendi B, Gardner T, Wasylink S, Malison RT, Sanacora G, Krystal JH, Coric V: N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl). 2006 Jan; 2005 Dec 22. PMID: 16374600
- Pittenger C, Krystal JH, Coric V: Initial evidence of the beneficial effects of glutamate-modulating agents in the treatment of self-injurious behavior associated with borderline personality disorder. J Clin Psychiatry. 2005 Nov. PMID: 16420092
- Pittenger C, Kelmendi B, Bloch M, Krystal JH, Coric V: Clinical treatment of obsessive compulsive disorder. Psychiatry (Edgmont). 2005 Nov. PMID: 21120095
- Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, Saksa J, Wu YT, Gueorguieva R, Sanacora G, Malison RT, Krystal JH: Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005 Sep 1. PMID: 15993857
- Etkin A, Pittenger C, Polan HJ, Kandel ER: Toward a neurobiology of psychotherapy: basic science and clinical applications. J Neuropsychiatry Clin Neurosci. 2005 Spring. PMID: 15939967
- Huang YY, Pittenger C, Kandel ER: A form of long-lasting, learning-related synaptic plasticity in the hippocampus induced by heterosynaptic low-frequency pairing. Proc Natl Acad Sci U S A. 2004 Jan 20; 2004 Jan 7. PMID: 14711997
- Pittenger C, Kandel ER: In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. Philos Trans R Soc Lond B Biol Sci. 2003 Apr 29. PMID: 12740123
- Kandel ER, Pittenger C: [Past and future studies of memory]. Kos. 2003 Apr. PMID: 12760381
- Barco A, Pittenger C, Kandel ER: CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets. 2003 Feb. PMID: 12556206
- Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H, Vronskaya S, Kandel ER: Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron. 2002 Apr 25. PMID: 11988175
- Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C, Kandel ER: Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron. 2001 Oct 11. PMID: 11604144
- Pittenger C: Communicating with our elderly. Contemp Longterm Care. 2001 Jan. PMID: 11209282
- Kandel ER, Pittenger C: The past, the future and the biology of memory storage. Philos Trans R Soc Lond B Biol Sci. 1999 Dec 29. PMID: 10670023
- Pittenger C, Kandel E: A genetic switch for long-term memory. C R Acad Sci III. 1998 Feb-Mar. PMID: 9759326
- Reagan MS, Pittenger C, Siede W, Friedberg EC: Characterization of a mutant strain of Saccharomyces cerevisiae with a deletion of the RAD27 gene, a structural homolog of the RAD2 nucleotide excision repair gene. J Bacteriol. 1995 Jan. PMID: 7814325
- Bardwell AJ, Bardwell L, Wang Z, Siede W, Reagan MS, Tomkinson AE, Friedberg AS, Pittenger C, Feaver WJ, Svejstrup J: Recent insights on DNA repair. The mechanism of damaged nucleotide excision in eukaryotes and its relationship to other cellular processes. Ann N Y Acad Sci. 1994 Jul 29. PMID: 8092684