Courtney A. Miller

Last updated
Courtney A. Miller
Courtney Miller (wiki).jpg
NationalityAmerican
Alma materUniversity of California, Santa Barbara, University of California, Irvine, University of Alabama Birmingham
Known forDiscovery that the drug Blebbistatin leads to long-lasting disruption in methamphetamine drug seeking
AwardsPECASE - Presidential Early Career Award for Scientists and Engineers) - awarded by President Obama, TSRI Outstanding Mentor Award, Most influential paper published by Neuron in 2007, Kauffman Fellow, Venture Capital Program, NIDA Young Investigator Award
Scientific career
FieldsNeuroscience
InstitutionsThe Scripps Research Institute, Florida

Courtney A. Miller is an American neuroscientist and Professor of the Department of Molecular Medicine at the Scripps Research Institute in Jupiter, Florida. Miller investigates the biological basis of neurological and neuropsychiatric diseases and develops novel therapeutics based on her mechanistic discoveries.

Contents

Early life and education

Miller completed her undergraduate degree at the University of California, Santa Barbara majoring in Biopsychology. [1] After graduating in 1999, Miller started her PhD in Neurobiology and Behavior at the University of California, Irvine. [2] Under the mentorship of Dr. John F. Marshall, Miller studied the biological basis of drug addiction in rodent models. [3] [4] Since relapse is common in drug abusers, Miller sought to understand the biological basis of this phenomenon. Miller first dissected the neural circuits that are activated during re-exposure to an environment previously associated with cocaine. [4] Miller found that, during expression of drug induced place preference, the Basolateral Amygdala complex provides more excitatory drive to the Nucleus Accumbens Core than the Prelimbic cortex. [4] In a first author paper in Neuron, Miller reported that inhibiting ERK kinase MEK prevents the activation of ERK in the Nucleus Accumbens Core and inhibits conditioned place preference. [3] Her findings suggested that memories of drug-cue pairings can be pharmacologically or therapeutically ameliorated to potentially reduce relapse in drug abusers. [3]

Miller completed her PhD in 2005 and then worked as a Research Scientist at Cenomed Pharmaceuticals. In 2006, Miller began a postdoctoral fellowship [5] at the University of Alabama Birmingham and held the title of scientific director of the Behavior Core at the University of Alabama Birmingham from 2006 to 2009. [2] At UAB, Miller studied neuroepigenetics and found that DNA methylation along with the process of histone acetylation regulates memory formation and synaptic plasticity. [6] Also while at UAB, Miller completed a degree in Technology Ventures at the UAB School of Business from 2007–2008. [2]

Career and research

In 2009, Miller was appointed an assistant professorship at The Scripps Research Institute in Jupiter, Florida. [2] In 2013, Miller was granted tenure and now remains at Scripps conducting research on neurological diseases with a specific focus on drug addiction and post-traumatic stress disorder. [1] [2] With her background in industry and business, Miller has a strong focus on making sure her research is translational and will progress towards the drug discovery pipeline. [2] [7]

Miller and her lab made a significant discovery in 2015 regarding the potential to target the actin cytoskeleton as a means to treat relapsing methamphetamine addiction. [8] [9] Miller found that inhibiting actin polymerization in the amygdala, with a non-muscle myosin II inhibitor, disrupted drug-seeking behavior. [8] In 2017, Miller and her group furthered these findings by exploring the effects of Blebbistatin, a small molecular non-muscle myosin II inhibitor, on methamphetamine-related memories compared to cocaine and morphine-related memories. [10] They found that the effects of Blebbistatin on memory disruption are specific to methamphetamine-related memories and they are amygdala dependent. [10] This finding will pave the way for specific therapeutic interventions for addiction that treatments that do not require re-exposure to the drug cues. [10] [11] For this discovery, Miller was honored with the Presidential Early Career Award and received a five-year research grant to support furthering her findings towards clinical trials. [5]

In 2019, Miller and her group found a microRNA in the amygdala that is specifically elevated after trauma. [12] They discovered this microRNA by sequencing RNA from the Basolateral Amygdala, a brain region known to be implicated in fear conditioning, to observe differences in microRNAs levels after fear conditioning. Fear conditioning is done in this experiment to model the biological processes that might occur after traumas that precede the development of post-traumatic stress disorder. Miller's results shows that the most robustly down-regulated microRNA after fear conditioning was mir-589-3p. [13] Miller and her group further found that inhibiting this microRNA interfered with expression and extinction of fear memories. [13] Interestingly, the difference in microRNA mir-598-3p level and the effect of its inhibition was only observed in male but not female mice. [13]

In addition to her translational research, Miller is a strong advocate for women in science and is the cofounder of the Professional Women's Nexus, an organization that provides a network for female professionals to connect and support each other in their career. [14] Miller has given many talks on how to foster early career success for women and in 2019 she organized the SFN Professional Development workshop “Addressing issues facing women in the early stages of their scientific career”. [15] [16]

Awards and achievements

Select publications

Related Research Articles

Dendritic spine Small protrusion on a dendrite that receives input from a single axon

A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head, and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons. It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.

Long-term potentiation Persistent strengthening of synapses based on recent patterns of activity

In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.

AMPA receptor

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel to be crystallized.

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

Spike-timing-dependent plasticity (STDP) is a biological process that adjusts the strength of connections between neurons in the brain. The process adjusts the connection strengths based on the relative timing of a particular neuron's output and input action potentials. The STDP process partially explains the activity-dependent development of nervous systems, especially with regard to long-term potentiation and long-term depression.

Tropomyosin Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in actin-based cytoskeletons.

Schaffer collaterals are axon collaterals given off by CA3 pyramidal cells in the hippocampus. These collaterals project to area CA1 of the hippocampus and are an integral part of memory formation and the emotional network of the Papez circuit, and of the hippocampal trisynaptic loop. It is one of the most studied synapses in the world and named after the Hungarian anatomist-neurologist Károly Schaffer.

c-Fos

In the fields of molecular biology and genetics, c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

Ca<sup>2+</sup>/calmodulin-dependent protein kinase II

Ca2+
/calmodulin-dependent protein kinase II
is a serine/threonine-specific protein kinase that is regulated by the Ca2+
/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+
homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.

SYNGAP1 Protein in Homo sapiens

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability, epilepsy, autism and sensory processing deficits.

FOSB

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.

Activity-regulated cytoskeleton-associated protein

Activity-regulated cytoskeleton-associated protein is a plasticity protein that in humans is encoded by the ARC gene. It was first characterized in 1995. ARC is a member of the immediate-early gene (IEG) family, a rapidly activated class of genes functionally defined by their ability to be transcribed in the presence of protein synthesis inhibitors. ARC mRNA is localized to activated synaptic sites in an NMDA receptor-dependent manner, where the newly translated protein is believed to play a critical role in learning and memory-related molecular processes. Arc protein is widely considered to be important in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunction in the production of Arc protein has been implicated as an important factor in understanding various neurological conditions, including amnesia, Alzheimer's disease, Autism spectrum disorders, and Fragile X syndrome. Along with other IEGs such as ZNF268 and HOMER1, ARC is also a significant tool for systems neuroscience as illustrated by the development of the cellular compartment analysis of temporal activity by fluorescence in situ hybridization, or catFISH technique.

Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Uwe Frey and Richard G. Morris; it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan.

Actin remodeling is a biochemical process in cells. In the actin remodeling of neurons, the protein actin is part of the process to change the shape and structure of dendritic spines. G-actin is the monomer form of actin, and is uniformly distributed throughout the axon and the dendrite. F-actin is the polymer form of actin, and its presence in dendritic spines is associated with their change in shape and structure. Actin plays a role in the formation of new spines as well as stabilizing spine volume increase. The changes that actin brings about lead to the formation of new synapses as well as increased cell communication.

Addiction A disease resulting in compulsive engagement in rewarding stimuli despite adverse consequences

Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences. Despite the involvement of a number of psychosocial factors, a biological process—one that is induced by repeated exposure to an addictive stimulus—is the core pathology that drives the development and maintenance of an addiction, according to the "brain disease model" of addiction. However, some scholars who study addiction argue that the brain disease model is incomplete and misleading.

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.

Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal behaviour. It seeks to explain how nurture shapes nature, where nature refers to biological heredity and nurture refers to virtually everything that occurs during the life-span. Behavioral epigenetics attempts to provide a framework for understanding how the expression of genes is influenced by experiences and the environment to produce individual differences in behaviour, cognition, personality, and mental health.

Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. The process of developing an addiction occurs through instrumental learning, which is otherwise known as operant conditioning.

Homosynaptic plasticity

Homosynaptic plasticity is one type of synaptic plasticity. Homosynaptic plasticity is input-specific, meaning changes in synapse strength occur only at post-synaptic targets specifically stimulated by a pre-synaptic target. Therefore, the spread of the signal from the pre-synaptic cell is localized.

Memory erasure is the selective artificial removal of memories or associations from the mind. Memory erasure has been shown to be possible in some experimental conditions; some of the techniques currently being investigated are: drug-induced amnesia, selective memory suppression, destruction of neurons, interruption of memory, reconsolidation, and the disruption of specific molecular mechanisms.

References

  1. 1 2 3 "Courtney Miller | Scripps Research". www.scripps.edu. Retrieved 2020-03-28.
  2. 1 2 3 4 5 6 "Courtney A. Miller, Ph.D." www.scripps.edu. Retrieved 2020-03-28.
  3. 1 2 3 Miller, Courtney A.; Marshall, John F. (2005-09-15). "Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory". Neuron. 47 (6): 873–884. doi:10.1016/j.neuron.2005.08.006. ISSN   0896-6273. PMID   16157281. S2CID   631951.
  4. 1 2 3 Miller, Courtney A.; Marshall, John F. (March 2005). "Altered Fos expression in neural pathways underlying cue-elicited drug seeking in the rat". The European Journal of Neuroscience. 21 (5): 1385–1393. doi:10.1111/j.1460-9568.2005.03974.x. ISSN   0953-816X. PMID   15813948. S2CID   24152704.
  5. 1 2 3 Institute, The Scripps Research. "Scripps Florida's Courtney Miller Wins Presidential Early Career Award". www.prnewswire.com. Retrieved 2020-03-28.
  6. Miller, Courtney A.; Campbell, Susan L.; Sweatt, J. David (May 2008). "DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity". Neurobiology of Learning and Memory. 89 (4): 599–603. doi:10.1016/j.nlm.2007.07.016. ISSN   1074-7427. PMC   2430891 . PMID   17881251.
  7. "Memory Research Offers Promise for a Meth Addiction Treatment". Psychiatry & Behavioral Health Learning Network. Retrieved 2020-03-28.
  8. 1 2 Young, Erica; Briggs, Sherri; A. Miller, Courtney (2015-05-29). "The Actin Cytoskeleton as a Therapeutic Target for the Prevention of Relapse to Methamphetamine Use". CNS & Neurological Disorders Drug Targets. 14 (6): 731–737. doi:10.2174/1871527314666150529145531. PMC   4641563 . PMID   26022262.
  9. "Managing Memories | Scripps Research". www.scripps.edu. Retrieved 2020-03-28.
  10. 1 2 3 Briggs, Sherri B.; Blouin, Ashley M.; Young, Erica J.; Rumbaugh, Gavin; Miller, Courtney A. (February 2017). "Memory disrupting effects of nonmuscle myosin II inhibition depend on the class of abused drug and brain region". Learning & Memory. 24 (2): 70–75. doi:10.1101/lm.043976.116. ISSN   1072-0502. PMC   5238718 . PMID   28096495.
  11. "Scripps team finds a drug that fights addiction by eliminating memories". FierceBiotech. Retrieved 2020-03-28.
  12. "Overcoming PTSD: Study reveals memory disruption drug target". EurekAlert!. Retrieved 2020-03-28.
  13. 1 2 3 Jones, Meghan E.; Sillivan, Stephanie E.; Jamieson, Sarah; Rumbaugh, Gavin; Miller, Courtney A. (September 2019). "microRNA mir-598-3p mediates susceptibility to stress enhancement of remote fear memory". Learning & Memory. 26 (9): 363–372. doi:10.1101/lm.048827.118. ISSN   1549-5485. PMC   6699414 . PMID   31416909.
  14. "Professional Women's Nexus: About Us". Professional Women's Nexus. Retrieved 2020-03-28.
  15. 1 2 "Addressing Issues Facing Women in the Early Stages of their Scientific Career". neuronline.sfn.org. Retrieved 2020-03-28.
  16. 1 2 3 4 5 "Courtney Miller | Scripps Research". www.scripps.edu. Retrieved 2020-03-28.
  17. "Michael Oldstone, Courtney Miller Named 2015 TSRI Outstanding Mentors". www.scripps.edu. Retrieved 2020-03-28.
  18. 1 2 3 4 5 6 7 "Courtney Miller | Scripps Research". www.scripps.edu. Retrieved 2020-03-30.