Calakos Lab

201E Bryan Research

Nicole Calakos, MD, PhD, PI

Email: nicole.calakos@duke.edu

Research Office: 919-684-2423

Location: 201E Bryan

We all know that as part of our daily lives we are constantly interacting with our environment - learning, adapting, establishing new memories and habits, and for better or for worse, forgetting as well. At the cellular level, these processes can be encoded by changes in the strength of synaptic transmission between neurons. The process by which neuronal connections change in response to experience is known as “synaptic plasticity” and this process is a major interest of our laboratory. Our goals are to understand the molecular mechanisms for synaptic plasticity and identify when these processes have gone awry in neurological diseases. In doing so, we will establish the necessary framework to target these processes for therapeutic interventions; potentially identifying novel and improved treatment options.

We focus these interests on the striatal circuitry of the basal ganglia. The striatum is a key entry point for cortical information into the basal ganglia. The basal ganglia are involved in a wide variety of behaviors because they are critical for our movement, including the learning of motor routines and when to call them into action. Disorders in this process have wide ranging manifestations and substantially contribute to diseases like Parkinson’s disease, OCD, dystonia, Tourette’s and addictive behavior.

Our lab has pioneered a number of molecular and circuit-cracking methodologies that have provided new views into the workings of the striatal circuitry and its plasticity rules. Our lab has deep expertise in electrophysiology and optical physiology (two photon calcium imaging) and state-of-the-art molecular genetic mouse modeling techniques. Yet, our insights are further amplified by the highly collaborative approach we have with colleagues at Duke and beyond.

To get a better view of how pathway balance in basal ganglia circuitry may be affected, our lab has developed tools and approaches that make it possible to study the function of striatal medium spiny neurons in the direct and indirect pathways simultaneously in living tissue (Shuen et al., 2008; Ade et al., 2011, O’Hare and Ade et al., 2016). We use them to identify functional differences between these two types of medium spiny neurons and their role in normal adaptive plasticity and disease processes.

In habit, we identified circuit predictors of behavior. These include some classic expectations for mechanisms of plasticity such as increased firing activity, but also some surprises, like finding shifts in the timing of firing between these two cell types (O’Hare and Ade et al., 2016) and that a key coordinator is an interneuron (O’Hare et al., eLife 2017).

In disease settings, we leverage the Sapap3 KO model to understand what causes repetitive, self-injurious behavior and anxiety-like behaviors (“OCD-like”). We find a central role for striatal group 1 metabotropic glutamate receptor overactivity (Ade et al., Biol. Psych. 2016). By developing a unique high-throughput screening assay for an inherited cause of the movement disorder, dystonia, we came to recognize that multiple forms of this disease were united by a common defect in signaling by the proteostasis pathway known as the “integrated stress response” or ISR (also eIF2alpha phosphorylation) (Rittiner and Caffall et al., Neuron 2016).

Currently, ISR research in the lab has markedly expanded to address both its basic mechanisms (Helseth and Hernandez-Martinez et al., Science 2021) and its translational potential (Caffall et al., Sci. Transl. Med. 2021) for dystonia, Parkinson’s and other brain diseases.

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Recent Posts

Event
Wednesday, April 20, 2022 - 12:00
103 Bryan
Victoria Hall and Matt Oliver

Please join us on Wednesday, April 20th at noon.

calakos and liddle headshots
News
Friday, October 29, 2021
By Will Alexander

Researchers at Duke University School of Medicine have been selected to lead two inter-institution team grants totaling $18 million to investigate Parkinson’s disease.

Event
Wednesday, September 22, 2021 - 12:00
DIBS Cube - Multi-purpose room
Elana Lockshin

PhD candidate Elana Lockshin (Calakos Lab) will present The role of the unfolded-protein-response in the dopaminergic system for proper locomotion and cognition in-person on Wed. Sept. 22 at noon.

calakos
News
Tuesday, May 4, 2021
By Karl Leif Bates

The discovery of a signaling pathway in the brain that could make mice into ‘superlearners’ understandably touched off a lot of excitement a few years back.

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