Scholars@Duke
Nicole Calakos

Nicole Calakos

Lincoln Financial Group Distinguished Professor of Neurobiology
Neurology, Movement Disorders
nicole.calakos@duke.edu
Duke Box 2900, Durham, NC 27710
311 Bryan Res Drive, Durham, NC 27710

Selected Publications

Emerging Molecular-Genetic Families in Dystonia: Endosome-Autophagosome-Lysosome and Integrated Stress Response Pathways.

Journal Article Mov Disord · January 2025 Advances in genetic technologies and disease modeling have greatly accelerated the pace of introducing and validating molecular-genetic contributors to disease. In dystonia, there is a growing convergence across multiple distinct forms of the disease onto ... Full text Link to item Cite

Motor network reorganization associated with rTMS-induced writing improvement in writer's cramp dystonia.

Journal Article Brain Stimul · 2025 BACKGROUND: Writer's cramp (WC) dystonia is an involuntary movement disorder with distributed abnormalities in the brain's motor network. Prior studies established the potential for repetitive transcranial magnetic stimulation (rTMS) to either premotor cor ... Full text Link to item Cite

The Perineuronal Net Protein Brevican Acts in Nucleus Accumbens Parvalbumin-Expressing Interneurons of Adult Mice to Regulate Excitatory Synaptic Inputs and Motivated Behaviors.

Journal Article Biol Psychiatry · November 1, 2024 BACKGROUND: Experience-dependent functional adaptation of nucleus accumbens (NAc) circuitry underlies the development and expression of reward-motivated behaviors. Parvalbumin-expressing GABAergic (gamma-aminobutyric acidergic) interneurons (PVINs) within ... Full text Link to item Cite

The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.

Journal Article Curr Opin Neurobiol · August 2024 The integrated stress response (ISR) is a highly conserved biochemical pathway that regulates protein synthesis. The ISR is activated in response to diverse stressors to restore cellular homeostasis. As such, the ISR is implicated in a wide range of diseas ... Full text Link to item Cite

The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia.

Journal Article J Clin Invest · April 1, 2024 The integrated stress response (ISR) is a highly conserved biochemical pathway involved in maintaining proteostasis and cell health in the face of diverse stressors. In this Review, we discuss a relatively noncanonical role for the ISR in neuromodulatory n ... Full text Link to item Cite

Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp.

Journal Article Mov Disord · January 2023 BACKGROUND: Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to th ... Full text Open Access Link to item Cite

Transcranial magnetic stimulation: the road to clinical therapy for dystonia

Journal Article Dystonia · January 1, 2023 Despite many research studies, transcranial magnetic stimulation (TMS) is not yet an FDA-approved clinical therapy for dystonia patients. This review describes the four major challenges that have historically hindered the clinical translation of TMS. The f ... Full text Open Access Cite

DYT-TOR1A genotype alters extracellular vesicle composition in murine cell model and shows potential for biomarker discovery

Journal Article Dystonia · January 1, 2023 Introduction: Biomarkers that can be used to identify patient subgroups with shared pathophysiology and/or that can be used as pharmacodynamic readouts of disease state are valuable assets for successful clinical trial design. In translational research for ... Full text Cite

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing.

Journal Article PLoS Comput Biol · June 2022 GABA is generally known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyperpolarizing membrane potential. However, GABAergic currents sometimes exhibit non-inhibitory effects, depending on the brain region, developme ... Full text Open Access Link to item Cite

Dataset on the mass spectrometry-based proteomic profiling of mouse embryonic fibroblasts from a wild type and DYT-TOR1A mouse model of dystonia, basally and during stress.

Journal Article Data Brief · December 2021 Here, we present quantitative subcellular compartment-specific proteomic data from wildtype and DYT-TOR1A heterozygous mouse embryonic fibroblasts (MEFs) basally and following thapsigargin (Tg) treatment [1]. In this experiment, we generated MEFs from wild ... Full text Link to item Cite

DYT-TOR1A subcellular proteomics reveals selective vulnerability of the nuclear proteome to cell stress.

Journal Article Neurobiol Dis · October 2021 TorsinA is a AAA+ ATPase that shuttles between the ER lumen and outer nuclear envelope in an ATP-dependent manner and is functionally implicated in nucleocytoplasmic transport. We hypothesized that the DYT-TOR1A dystonia disease-causing variant, ΔE TorsinA ... Full text Link to item Cite

The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.

Journal Article Sci Transl Med · August 18, 2021 Dystonias are a group of chronic movement-disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, w ... Full text Link to item Cite

Cholinergic neurons constitutively engage the ISR for dopamine modulation and skill learning in mice.

Journal Article Science · April 23, 2021 The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning, and memory. We developed a reporter, SPOTlight, for brainwide imaging of ISR state with cellular resolution. Unex ... Full text Link to item Cite

Treatment of diaphragmatic dystonia with pallidal deep brain stimulation.

Journal Article BMJ Case Rep · March 25, 2021 We present the case of a 70-year-old woman with treatment-refractory diaphragmatic dystonia. Patient initially presented with blepharospasms followed by development of involuntary inspiratory spasms during speech. Her symptoms were drug-refractory, and she ... Full text Link to item Cite

Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor.

Journal Article Tremor Other Hyperkinet Mov (N Y) · August 14, 2020 HIGHLIGHTS: This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective ha ... Full text Link to item Cite

Defining research priorities in dystonia.

Journal Article Neurology · March 24, 2020 OBJECTIVE: Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities. METHODS: T ... Full text Link to item Cite

Parvalbumin Interneurons of the Mouse Nucleus Accumbens are Required For Amphetamine-Induced Locomotor Sensitization and Conditioned Place Preference.

Journal Article Neuropsychopharmacology · April 2018 To determine the requirement for parvalbumin (PV) expressing GABAergic interneurons of the nucleus accumbens (NAc) in the behavioral adaptations induced by amphetamine (AMPH), we blocked synaptic vesicle release from these neurons using Cre-inducible viral ... Full text Link to item Cite

Recent Insights into Corticostriatal Circuit Mechanisms underlying Habits: Invited review for Current Opinions in Behavioral Sciences.

Journal Article Curr Opin Behav Sci · April 2018 Habits have been studied for decades, but it was not until recent years that experiments began to elucidate the underlying cellular and circuit mechanisms. The latest experiments have been enabled by advances in cell-type specific monitoring and manipulati ... Full text Link to item Cite

Striatal fast-spiking interneurons selectively modulate circuit output and are required for habitual behavior.

Journal Article Elife · September 5, 2017 Habit formation is a behavioral adaptation that automates routine actions. Habitual behavior correlates with broad reconfigurations of dorsolateral striatal (DLS) circuit properties that increase gain and shift pathway timing. The mechanism(s) for these ci ... Full text Link to item Cite

Seq-ing the Circuit Logic of the Basal Ganglia.

Journal Article Trends Neurosci · June 2017 Recently, Wallace et al. (2017) provide an unprecedented view of the layers of molecular, cellular and circuit complexity involving a basal ganglia output structure, the entopeduncular nucleus. Their findings lend order to chaos by revealing how molecularl ... Full text Link to item Cite

Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.

Journal Article Neuron · December 21, 2016 Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signal ... Full text Link to item Cite

Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice.

Journal Article Biol Psychiatry · October 1, 2016 BACKGROUND: Development of treatments for obsessive-compulsive disorder (OCD) is hampered by a lack of mechanistic understanding about this prevalent neuropsychiatric condition. Although circuit changes such as elevated frontostriatal activity are linked t ... Full text Link to item Cite

Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models.

Journal Article Neurobiol Dis · September 2016 Rare de novo mutations in genes associated with inherited Mendelian disorders are potential contributors to sporadic disease. DYT1 dystonia is an autosomal dominant, early-onset, generalized dystonia associated with an in-frame, trinucleotide deletion (n. ... Full text Link to item Cite

Pathway-Specific Striatal Substrates for Habitual Behavior.

Journal Article Neuron · February 3, 2016 The dorsolateral striatum (DLS) is implicated in habit formation. However, the DLS circuit mechanisms underlying habit remain unclear. A key role for DLS is to transform sensorimotor cortical input into firing of output neurons that project to the mutually ... Full text Link to item Cite

Spotlight on movement disorders: What optogenetics has to offer.

Journal Article Mov Disord · April 15, 2015 Elucidating the neuronal mechanisms underlying movement disorders is a major challenge because of the intricacy of the relevant neural circuits, which are characterized by diverse cell types and complex connectivity. A major limitation of traditional techn ... Full text Link to item Cite

Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells.

Journal Article J Clin Invest · February 2015 Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroen ... Full text Open Access Link to item Cite

Astrocytes refine cortical connectivity at dendritic spines.

Journal Article Elife · December 17, 2014 During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. ... Full text Open Access Link to item Cite

Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder.

Journal Article Biol Psychiatry · April 15, 2014 BACKGROUND: Synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) is an excitatory postsynaptic protein implicated in the pathogenesis of obsessive-compulsive behaviors. In mice, genetic deletion of Sapap3 causes obses ... Full text Link to item Cite

MeCP2 phosphorylation limits psychostimulant-induced behavioral and neuronal plasticity.

Journal Article J Neurosci · March 26, 2014 The methyl-DNA binding protein MeCP2 is emerging as an important regulator of drug reinforcement processes. Psychostimulants induce phosphorylation of MeCP2 at Ser421; however, the functional significance of this posttranslational modification for addictiv ... Full text Link to item Cite

Presynaptic long-term plasticity.

Journal Article Front Synaptic Neurosci · October 17, 2013 Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now ... Full text Link to item Cite

A Gαs DREADD mouse for selective modulation of cAMP production in striatopallidal neurons.

Journal Article Neuropsychopharmacology · April 2013 Here, we describe a newly generated transgenic mouse in which the Gs DREADD (rM3Ds), an engineered G protein-coupled receptor, is selectively expressed in striatopallidal medium spiny neurons (MSNs). We first show that in vitro, rM3Ds can couple to Gαolf a ... Full text Link to item Cite

A multimodal micro-optrode combining field and single unit recording, multispectral detection and photolabeling capabilities.

Journal Article PLoS One · 2013 Microelectrodes have been very instrumental and minimally invasive for in vivo functional studies from deep brain structures. However they are limited in the amount of information they provide. Here, we describe a, aluminum-coated, fibre optic-based glass ... Full text Link to item Cite

Botulinum toxin: From molecule to clinic

Chapter · January 1, 2012 INTRODUCTION Treatment with botulinum toxin has fast become the mainstay for the management of focal dystonias. Its wide utility lies in the fact that, by harnessing the chemical denervation properties of this toxin, one can functionally weaken the endpoin ... Full text Cite

Sapap3 deletion causes mGluR5-dependent silencing of AMPAR synapses.

Journal Article J Neurosci · November 16, 2011 Synaptic transmission mediated by AMPA-type glutamate receptors (AMPARs) is regulated by scaffold proteins in the postsynaptic density. SAP90/PSD-95-associated protein 3 (SAPAP3) is a scaffold protein that is highly expressed in striatal excitatory synapse ... Full text Link to item Cite

Munc13-1 is required for presynaptic long-term potentiation.

Journal Article J Neurosci · August 17, 2011 Long-lasting forms of synaptic plasticity involve modification of presynaptic strength in many brain regions. Although a presynaptic site for expression is well established, the detailed molecular mechanisms that lead to sustained changes in neurotransmitt ... Full text Link to item Cite

Sapap3 deletion anomalously activates short-term endocannabinoid-mediated synaptic plasticity.

Journal Article J Neurosci · June 29, 2011 Retrograde synaptic signaling by endocannabinoids (eCBs) is a widespread mechanism for activity-dependent inhibition of synaptic strength in the brain. Although prevalent, the conditions for eliciting eCB-mediated synaptic depression vary among brain circu ... Full text Link to item Cite

An Improved BAC Transgenic Fluorescent Reporter Line for Sensitive and Specific Identification of Striatonigral Medium Spiny Neurons.

Journal Article Front Syst Neurosci · 2011 The development of BAC transgenic mice expressing promoter-specific fluorescent reporter proteins has been a great asset for neuroscience by enabling detection of neuronal subsets in live tissue. For the study of basal ganglia physiology, reporters driven ... Full text Link to item Cite

Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia.

Journal Article J Med Genet · September 2010 BACKGROUND: TOR1A encodes a chaperone-like AAA-ATPase whose Delta GAG (Delta E) mutation is responsible for an early onset, generalised dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalised dystonia (DYT1), a potenti ... Full text Link to item Cite

Acute in vivo genetic rescue demonstrates that phosphorylation of RIM1alpha serine 413 is not required for mossy fiber long-term potentiation.

Journal Article J Neurosci · February 17, 2010 While presynaptic, protein kinase A (PKA)-dependent, long-term plasticity has been described in numerous brain regions, the target(s) of PKA and the molecular mechanisms leading to sustained changes in neurotransmitter release remain elusive. Here, we acut ... Full text Link to item Cite

Confocal Analysis of Cholinergic and Dopaminergic Inputs onto Pyramidal Cells in the Prefrontal Cortex of Rodents.

Journal Article Front Neuroanat · 2010 Cholinergic and dopaminergic projections to the rat medial prefrontal cortex (mPFC) are both involved in cognitive functions including attention. These neuronal systems modulate mPFC neuronal activity mainly through diffuse transmission. In order to better ... Full text Link to item Cite

[SY5.1]: Synaptic and circuitry mechanisms of obsessive compulsive‐like behaviors in mice

Journal Article International Journal of Developmental Neuroscience · December 2008 Full text Cite

Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice.

Journal Article Nature · August 23, 2007 Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although t ... Full text Link to item Cite

Botulinum toxin: From molecule to clinic

Chapter · January 1, 2006 Treatment with botulinum toxin has fast become the mainstay for the management of focal dystonias. Its wide utility lies in the fact that, by harnessing the chemical denervation properties of this toxin, one can functionally weaken the endpoint of dystonia ... Cite

Generation of silent synapses by acute in vivo expression of CaMKIV and CREB.

Journal Article Neuron · March 3, 2005 The transcription factor CREB is critical for several forms of experience-dependent plasticity in a range of species and is commonly activated in neurons by calcium/calmodulin-dependent protein kinase IV (CaMKIV). Surprisingly, little is known about the ne ... Full text Link to item Cite

Multiple roles for the active zone protein RIM1alpha in late stages of neurotransmitter release.

Journal Article Neuron · June 24, 2004 The active zone protein RIM1alpha interacts with multiple active zone and synaptic vesicle proteins and is implicated in short- and long-term synaptic plasticity, but it is unclear how RIM1alpha's biochemical interactions translate into physiological funct ... Full text Link to item Cite

Cortical MRI findings associated with rapid correction of hyponatremia.

Journal Article Neurology · October 10, 2000 The authors describe two patients with clinical manifestations of the osmotic demyelination syndrome (ODS) and unusual MRI findings of gadolinium-enhancing peripheral cortical abnormalities. They propose that these represent extrapontine manifestations of ... Full text Link to item Cite

Nitric oxide modulates synaptic vesicle docking fusion reactions.

Journal Article Neuron · June 1996 Nitric oxide (NO) stimulates calcium-independent neurotransmitter release from synaptosomes. NO-stimulated release was found to be inhibited by Botulinum neurotoxins that inactivate the core complex of synaptic proteins involved in the docking and fusion o ... Full text Link to item Cite

Synaptic vesicle biogenesis, docking, and fusion: a molecular description.

Journal Article Physiol Rev · January 1996 Secretion of neurotransmitter is the primary means of intercellular communication within the nervous system. This process is regulated by a highly orchestrated cycle of membrane trafficking within the presynaptic nerve terminal. Characterization of protein ... Full text Link to item Cite

MOLECULAR MECHANISMS OF SYNAPTIC TRANSMISSION

Conference FASEB JOURNAL · April 24, 1995 Link to item Cite

Vesicle-associated membrane protein and synaptophysin are associated on the synaptic vesicle.

Journal Article J Biol Chem · October 7, 1994 The synaptic vesicle membrane protein VAMP (vesicle-associated membrane protein or synaptobrevin) has been implicated in synaptic vesicle docking and fusion. Synaptophsin (p38), also a synaptic vesicle membrane protein, has four transmembrane domains and m ... Link to item Cite

Specificity and regulation of a synaptic vesicle docking complex.

Journal Article Neuron · August 1994 Synaptic vesicles are proposed to dock at the presynaptic plasma membrane through the interaction of two integral membrane proteins of synaptic vesicles, VAMP and synaptotagmin, and two plasma membrane proteins, syntaxin and SNAP-25. We have characterized ... Full text Link to item Cite

Protein-protein interactions contributing to the specificity of intracellular vesicular trafficking.

Journal Article Science · February 25, 1994 Intracellular vesicles destined to fuse with the plasma membrane and secrete their contents must have a mechanism for specifically interacting with the appropriate target membrane. Such a mechanism is now suggested by the demonstration of specific interact ... Full text Link to item Cite

PROTEIN DOMAINS IMPORTANT FOR TARGETING OF THE SYNAPTIC VESICLE PROTEIN, VAMP

Conference JOURNAL OF CELLULAR BIOCHEMISTRY · January 26, 1993 Link to item Cite

Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones.

Journal Article Science · July 10, 1992 Synaptic vesicles store neurotransmitters that are released during calcium-regulated exocytosis. The specificity of neurotransmitter release requires the localization of both synaptic vesicles and calcium channels to the presynaptic active zone. Two 35-kil ... Full text Link to item Cite

Synaptic vesicle membrane proteins interact to form a multimeric complex.

Journal Article J Cell Biol · February 1992 Potential interactions between membrane components of rat brain synaptic vesicles were analyzed by detergent solubilization followed by size fractionation or immunoprecipitation. The behavior of six synaptic vesicle membrane proteins as well as a plasma me ... Full text Link to item Cite

Does compliance mismatch alone cause neointimal hyperplasia?

Journal Article J Vasc Surg · January 1989 To define the relationship between compliance mismatch and the development of neointimal hyperplasia, one 3 cm segment of common iliac artery was externally banded in seven dogs, thereby fixing the arterial diameter at end diastole. To quantify compliance, ... Link to item Cite