Christine Ann Denny

Last updated
Christine Ann Denny
NationalityAmerican
Alma materBoston College
Known forArcCreERT2 transgenic mouse line for memory tracing
AwardsNIH Early Independence Award, ELabNYC Fellow, Inductee into the Lyndhurst High School Academic Hall Of Fame, Brain & Behavior Research Foundation NARSAD Young Investigator Award, American Society for Neurochemistry Travel Award, Molecular and Cellular Cognition Society Young Travel Fellowship
Scientific career
FieldsNeuroscience
InstitutionsColumbia University

Christine Denny is an American neuroscientist and associate professor of Clinical Neurobiology in Psychiatry in the Department of Psychiatry at Columbia University Irving Medical Center in New York City. Denny investigates the molecular mechanisms underlying learning and memory. She developed a novel technique to label neurons that encode specific memories. She used this technique to probe what happens to hippocampal memory traces in different disease states.

Contents

Early life and education

Denny grew up in Lyndhurst, New Jersey and attended Lyndhurst High School. [1] Denny excelled in her academic pursuits in high school and received multiple scholarships, was recognized for her leadership at the state level, and graduated as class Salutatorian. [1] Denny was also actively involved in athletics and received varsity letters in volleyball and track and field. [1]

After graduating from Lyndhurst in 2001, Denny then pursued her undergraduate studies at Boston College where she received a Bachelors of Science majoring in Biological Sciences and minoring in Theology. [1] While at Boston College, Denny continued to excel in academics as she maintained Honor and Dean's List standing but she also became interested in research and received an Advanced Undergraduate Research Fellowship to support her research. In 2004, Denny began roles as a teaching assistant and laboratory instructor at Boston College. [1] After she graduated in 2005, Denny continued in academia pursuing a master's degree in biology at Boston College. [2] While at Boston College, Denny worked under the mentorship of Thomas N. Seyfried studying lipid storage diseases and metabolic therapies to treat brain diseases. [3] In 2007, Denny published a first author paper in the Journal of Neurochemistry highlighting a model system for assessing retinal pathobiology and therapies for ganglioside storage diseases. [4] Denny also explored lipid abnormalities in mouse models of Rett syndrome [5] as well as the effects of ketogenic diets on alleviating symptoms of Sandhoff disease, a ganglioside storage disease. [6]

Denny then pursued a PhD in neuroscience at Columbia University under the mentorship of Dr. Rene Hen. [7] Denny first explored hippocampal neurogenesis and published a first author paper in 2010 showing that inhibiting neurogenesis increases novel object exploration and impairs one trial contextual fear-learning in mice suggesting an important role for adult born neurons in cognitive function. [8] Denny then began to exploring the idea of memory traces, cells in the brain where memories are stored, and tried to tag these memory traces in the dentate gyrus and CA3 regions of the hippocampus. [9] She was able to develop a genetic tool that enabled her to fluorescently tag neurons that were activated in specific memories. [9] Since her tool enabled long term labelling of memory associated neurons, she is able to observe memory traces over time and reported that memory traces become more faint over time even though learned behaviors persist. [7] Her findings highlights the possibility that these memory traces are being redistributed to areas other than the hippocampus for even longer-term storage. [7] She further used optogenetics to silence the cells involved the memory trace of contextual fear learning and showed that silencing inhibited expression of learned fear memories. [9] Her work led to a first author paper in Neuron in 2014. Denny completed her PhD in 2012, and remained at Columbia to conduct postdoctoral work until 2013 in the Hen Laboratory. [1]

Career and research

After receiving an NIH DP5 Early Independence Award, [10] Denny started her own lab at Columbia University in 2013 and began her position as an assistant professor of Clinical Neurobiology in Psychiatry. [2] Denny also holds the title of Research Scientist V in the Division of Systems Neuroscience at the New York State Psychiatric Institute. [2] The research focus of the Denny Lab is understanding the neural basis of learning and memory and how these processes are altered in disease states such as Alzheimer's disease and depression. [10] Denny's Lab uses the transgenic mice she helped develop in graduate school, ArcCreERT2 mice, to label memory traces and investigate what happens to them in disease models. In 2015, Denny and her colleagues optimized their technique by using a more specific and time limited selective estrogen receptor modulator called 4-hydroxy tamoxifen instead of regular tamoxifen. [11] This technique refined the ability to selectively label memory traces. [11] Using this technique, Denny labelled neurons involved in novel social interaction and found that reactivation of these neurons during expression of learned fear responses decreases freezing. [12] These findings suggested the possibility of social neural circuits within the infralimbic prefrontal cortex as a therapeutic target for ameliorating anxiety or other disorders of learned fear associations. [12] In 2017, Denny then crossed her ArcCreERT2 mouse line with an Alzheimer's model mouse line (APP/PS1) to look at memory traces in a neurodegenerative disease model. When they specifically reactivated neuronal ensembles in the dentate gyrus implicated in contextual fear conditioning in APP/PS1 mice, they found a significant increase in memory retrieval compared to controls suggesting that activated previously learned memory traces in the dentate gyrus might rescue memory loss phenotypes in disease. [13]

Denny's lab also investigates small molecule prophylactics for stress-induced depressive-like behavior. [14] Since psychiatric illnesses often follow stressful events, Denny has proposed the importance of prophylactic therapies in preventing susceptible individuals from developing psychiatric disorders after stressful events. One of the molecules Denny has been exploring the prophylactic therapeutic benefit of is ketamine, a fast acting antidepressant. [14] In 2015, Denny found that when ketamine is administered one week prior to various stress paradigms in mice, the effects of the stress paradigm are ameliorated and they do not show as robust depressive phenotypes. [15] In a follow-up paper in 2017, Denny and her lab found that administering ketamine right before or right after a fearful event did not protect against fearful events, while administration one week before a stressful event still seemed to provide prophylactic effects and decrease fear responses. [16] After these findings, Denny was interested in looking at the markers of stress resilience following ketamine treatment. [17] In a Nature paper in 2018, Denny found 8 metabolites that were changed in the prefrontal cortex and hippocampus after ketamine administration. One novel finding was that precursors to inhibitory neurotransmitters were increased whereas those for excitatory neurotransmitters were decreased. [17] This was one of the first findings showing a substrate for the prophylactic effects of ketamine on stress-induced depression. [17] Denny then looked at another prophylactic in comparison to ketamine, prucalopride - a 5-HT4Rgonist, and found that both have the ability to decrease stress-induced depressive-like behaviors and both alter AMPAR mediated synaptic transmission in the CA3 of the hippocampus. [18]

Awards and honors

Publications

Related Research Articles

<span class="mw-page-title-main">Hippocampus</span> Vertebrate brain region involved in memory consolidation

The hippocampus is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. The hippocampus is located in the allocortex, with neural projections into the neocortex, in humans as well as other primates. The hippocampus, as the medial pallium, is a structure found in all vertebrates. In humans, it contains two main interlocking parts: the hippocampus proper, and the dentate gyrus.

<span class="mw-page-title-main">Limbic system</span> Set of brain structures involved in emotion and motivation

The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.

<span class="mw-page-title-main">Dentate gyrus</span> Region of the hippocampus in the brain

The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute to the formation of new episodic memories, the spontaneous exploration of novel environments and other functions.

<span class="mw-page-title-main">Fear conditioning</span> Behavioral paradigm in which organisms learn to predict aversive events

Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus is associated with a particular neutral context or neutral stimulus, resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus. Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).

<span class="mw-page-title-main">Adult neurogenesis</span> Generating of neurons from neural stem cells in adults

Adult neurogenesis is the process in which neurons are generated from neural stem cells in the adult. This process differs from prenatal neurogenesis.

<span class="mw-page-title-main">Place cell</span> Place-activated hippocampus cells found in some mammals

A place cell is a kind of pyramidal neuron in the hippocampus that becomes active when an animal enters a particular place in its environment, which is known as the place field. Place cells are thought to act collectively as a cognitive representation of a specific location in space, known as a cognitive map. Place cells work with other types of neurons in the hippocampus and surrounding regions to perform this kind of spatial processing. They have been found in a variety of animals, including rodents, bats, monkeys and humans.

<span class="mw-page-title-main">Septal area</span> Area in the lower, posterior part of the medial surface of the frontal lobe

The septal area, consisting of the lateral septum and medial septum, is an area in the lower, posterior part of the medial surface of the frontal lobe, and refers to the nearby septum pellucidum.

Elizabeth Gould is an American neuroscientist and the Dorman T. Warren Professor of Psychology at Princeton University. She was an early investigator of adult neurogenesis in the hippocampus, a research area that continues to be controversial. In November 2002, Discover magazine listed her as one of the 50 most important women scientists.

<span class="mw-page-title-main">Subgranular zone</span>

The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.

Radiation-induced cognitive decline describes the possible correlation between radiation therapy and cognitive impairment. Radiation therapy is used mainly in the treatment of cancer. Radiation therapy can be used to cure, care or shrink tumors that are interfering with quality of life. Sometimes radiation therapy is used alone; other times it is used in conjunction with chemotherapy and surgery. For people with brain tumors, radiation can be an effective treatment because chemotherapy is often less effective due to the blood–brain barrier. Unfortunately for some patients, as time passes, people who received radiation therapy may begin experiencing deficits in their learning, memory, and spatial information processing abilities. The learning, memory, and spatial information processing abilities are dependent on proper hippocampus functionality. Therefore, any hippocampus dysfunction will result in deficits in learning, memory, and spatial information processing ability.

The cellular transcription factor CREB helps learning and the stabilization and retrieval of fear-based, long-term memories. This is done mainly through its expression in the hippocampus and the amygdala. Studies supporting the role of CREB in cognition include those that knock out the gene, reduce its expression, or overexpress it.

<span class="mw-page-title-main">Wim Crusio</span> Dutch behavioral neurogeneticist

Wim E. Crusio is a Dutch behavioral neurogeneticist and a directeur de recherche with the French National Centre for Scientific Research in Talence, France.

<span class="mw-page-title-main">Eomesodermin</span> Protein-coding gene in the species Homo sapiens

Eomesodermin also known as T-box brain protein 2 (Tbr2) is a protein that in humans is encoded by the EOMES gene.

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.

Endogenous regeneration in the brain is the ability of cells to engage in the repair and regeneration process. While the brain has a limited capacity for regeneration, endogenous neural stem cells, as well as numerous pro-regenerative molecules, can participate in replacing and repairing damaged or diseased neurons and glial cells. Another benefit that can be achieved by using endogenous regeneration could be avoiding an immune response from the host.

<span class="mw-page-title-main">ALTO-100</span> BDNF-modulating drug for depression and PTSD

ALTO-100, previously known as NSI-189, is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD). There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration. It is taken by mouth.

Epigenetics of depression is the study of how epigenetics contribute to depression.

Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.

Attila Losonczy is a Hungarian neuroscientist, Professor of Neuroscience at Columbia University Medical Center. Losonczy's main area of research is on the relationship between neural networks and behavior, specifically with regard to learning in the hippocampus.

<span class="mw-page-title-main">Neurogenesis hypothesis of depression</span> Theory of depression

Adult neurogenesis is the process by which functional, mature neurons are produced from neural stem cells (NSCs) in the adult brain. In most mammals, including humans, it only occurs in the subgranular zone of the hippocampus, and in the olfactory bulb. The neurogenesis hypothesis of depression proposes that major depressive disorder is caused, at least partly, by impaired neurogenesis in the subgranular zone of the hippocampus.

References

  1. 1 2 3 4 5 6 7 8 9 "Lyndhurst High School". www.lyndhurstschools.net. Retrieved 2020-04-05.
  2. 1 2 3 "Editorial Board". portlandpress.com. Retrieved 2020-04-05.
  3. ↑ "Thomas N. Seyfried - Biology - Morrissey College of Arts and Sciences - Boston College". www.bc.edu. Retrieved 2020-04-05.
  4. ↑ Denny, Christine A.; Alroy, Joseph; Pawlyk, Basil S.; Sandberg, Michael A.; D’Azzo, Alessandra; Seyfried, Thomas N. (2007). "Neurochemical, morphological, and neurophysiological abnormalities in retinas of Sandhoff and GM1 gangliosidosis mice". Journal of Neurochemistry. 101 (5): 1294–1302. doi:10.1111/j.1471-4159.2007.04525.x. ISSN   1471-4159. PMID   17442056. S2CID   17052020.
  5. ↑ Seyfried, Thomas N.; Heinecke, Karie A.; Mantis, John G.; Denny, Christine A. (2008-11-11). "Brain Lipid Analysis in Mice with Rett Syndrome". Neurochemical Research. 34 (6): 1057–65. doi:10.1007/s11064-008-9874-7. ISSN   1573-6903. PMC   4286142 . PMID   19002580.
  6. ↑ Denny, Christine A.; Heinecke, Karie A.; Kim, Youngho P.; Baek, Rena C.; Loh, Katrina S.; Butters, Terry D.; Bronson, Roderick T.; Platt, Frances M.; Seyfried, Thomas N. (2010). "Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice". Journal of Neurochemistry. 113 (6): 1525–1535. doi: 10.1111/j.1471-4159.2010.06733.x . ISSN   1471-4159. PMID   20374428. S2CID   40953804.
  7. 1 2 3 cmm_admin (2014-06-01). "The Optogenetics Revolution". Columbia Medicine Magazine. Retrieved 2020-04-05.
  8. ↑ Denny, Christine A.; Burghardt, Nesha S.; Schachter, Daniel M.; Hen, René; Drew, Michael R. (2012). "4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning". Hippocampus. 22 (5): 1188–1201. doi:10.1002/hipo.20964. ISSN   1098-1063. PMC   3193906 . PMID   21739523.
  9. 1 2 3 Denny, Christine A.; Kheirbek, Mazen A.; Alba, Eva L.; Tanaka, Kenji F.; Brachman, Rebecca A.; Laughman, Kimberly B.; Tomm, Nicole K.; Turi, Gergely F.; Losonczy, Attila; Hen, René (2014-07-02). "Hippocampal Memory Traces Are Differentially Modulated by Experience, Time, and Adult Neurogenesis". Neuron. 83 (1): 189–201. doi: 10.1016/j.neuron.2014.05.018 . ISSN   0896-6273. PMC   4169172 . PMID   24991962.
  10. 1 2 "Christine Ann Denny, PhD -- Honored Guest Lecturer". conference.neuromodulation.org. Retrieved 2020-04-05.
  11. 1 2 Cazzulino, Alejandro S.; Martinez, Randy; Tomm, Nicole K.; Denny, Christine A. (2016). "Improved specificity of hippocampal memory trace labeling". Hippocampus. 26 (6): 752–762. doi:10.1002/hipo.22556. ISSN   1098-1063. PMC   4867142 . PMID   26662713.
  12. 1 2 Donaldson, Zoe; Hen, René; Gutzeit, Vanessa; Santos, Tabia L.; Sadsad, Meghin; Denny, Christine A. (2016-10-01). "25.2 Social Buffering of Conditioned and Innate Fear Responses". Journal of the American Academy of Child & Adolescent Psychiatry. 55 (10): S297. doi:10.1016/j.jaac.2016.07.262. ISSN   0890-8567.
  13. ↑ Perusini, Jennifer N.; Cajigas, Stephanie A.; Cohensedgh, Omid; Lim, Sean C.; Pavlova, Ina P.; Donaldson, Zoe R.; Denny, Christine A. (2017). "Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice". Hippocampus. 27 (10): 1110–1122. doi:10.1002/hipo.22756. ISSN   1098-1063. PMC   5610644 . PMID   28667669.
  14. 1 2 "The Denny Laboratory" . Retrieved 2020-04-05.
  15. ↑ Brachman, Rebecca A.; McGowan, Josephine C.; Perusini, Jennifer N.; Lim, Sean C.; Pham, Thu Ha; Faye, Charlene; Gardier, Alain M.; Mendez-David, Indira; David, Denis J.; Hen, René; Denny, Christine A. (2016-05-01). "Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior". Biological Psychiatry. 79 (9): 776–786. doi:10.1016/j.biopsych.2015.04.022. ISSN   1873-2402. PMC   4633406 . PMID   26037911.
  16. ↑ McGowan, Josephine C; LaGamma, Christina T; Lim, Sean C; Tsitsiklis, Melina; Neria, Yuval; Brachman, Rebecca A; Denny, Christine A (July 2017). "Prophylactic Ketamine Attenuates Learned Fear". Neuropsychopharmacology. 42 (8): 1577–1589. doi:10.1038/npp.2017.19. ISSN   0893-133X. PMC   5518899 . PMID   28128336.
  17. 1 2 3 McGowan, Josephine C.; Hill, Collin; Mastrodonato, Alessia; LaGamma, Christina T.; Kitayev, Alexander; Brachman, Rebecca A.; Narain, Niven R.; Kiebish, Michael A.; Denny, Christine A. (August 2018). "Prophylactic ketamine alters nucleotide and neurotransmitter metabolism in brain and plasma following stress". Neuropsychopharmacology. 43 (9): 1813–1821. doi: 10.1038/s41386-018-0043-7 . ISSN   1740-634X. PMC   6046049 . PMID   29599484.
  18. ↑ Chen, Briana K.; Mendez-David, Indira; Luna, Victor M.; Faye, Charlène; Gardier, Alain M.; David, Denis J.; Denny, Christine A. (February 2020). "Prophylactic efficacy of 5-HT 4 R agonists against stress". Neuropsychopharmacology. 45 (3): 542–552. doi:10.1038/s41386-019-0540-3. ISSN   1740-634X. PMC   6969048 . PMID   31600767.
  19. 1 2 "Speakers". Women in Science at Columbia. 2018-04-03. Retrieved 2020-04-05.
  20. ↑ "NIH Director's Early Independence Award Program - 2013 Award Recipients | NIH Common Fund". commonfund.nih.gov. 18 September 2018. Retrieved 2020-04-05.
  21. 1 2 "Publications | The Denny Laboratory" . Retrieved 2020-04-05.
  22. ↑ Root, Cory M.; Denny, Christine A.; Hen, René; Axel, Richard (2014-11-13). "The participation of cortical amygdala in innate, odour-driven behaviour". Nature. 515 (7526): 269–273. Bibcode:2014Natur.515..269R. doi:10.1038/nature13897. ISSN   1476-4687. PMC   4231015 . PMID   25383519.
  23. ↑ Denny, Christine A.; Kheirbek, Mazen A.; Alba, Eva L.; Tanaka, Kenji F.; Brachman, Rebecca A.; Laughman, Kimberly B.; Tomm, Nicole K.; Turi, Gergely F.; Losonczy, Attila; Hen, René (2014-07-02). "Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis". Neuron. 83 (1): 189–201. doi:10.1016/j.neuron.2014.05.018. ISSN   1097-4199. PMC   4169172 . PMID   24991962.
  24. ↑ Oury, Franck; Khrimian, Lori; Denny, Christine A.; Gardin, Antoine; Chamouni, Alexandre; Goeden, Nick; Huang, Yung-yu; Lee, Hojoon; Srinivas, Prashanth; Gao, Xiao-Bing; Suyama, Shigetomo (2013-09-26). "Maternal and Offspring Pools of Osteocalcin Influence Brain Development and Functions". Cell. 155 (1): 228–241. doi: 10.1016/j.cell.2013.08.042 . ISSN   0092-8674. PMC   3864001 . PMID   24074871.
  25. ↑ Denny, Christine A.; Burghardt, Nesha S.; Schachter, Daniel M.; Hen, René; Drew, Michael R. (May 2012). "4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning". Hippocampus. 22 (5): 1188–1201. doi:10.1002/hipo.20964. ISSN   1098-1063. PMC   3193906 . PMID   21739523.
  26. ↑ Drew, Michael R.; Denny, Christine A.; Hen, Rene (August 2010). "Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning". Behavioral Neuroscience. 124 (4): 446–454. doi:10.1037/a0020081. ISSN   1939-0084. PMC   2925248 . PMID   20695644.
  27. ↑ Pollak, Daniela D.; Monje, Francisco J.; Zuckerman, Lee; Denny, Christine A.; Drew, Michael R.; Kandel, Eric R. (2008-10-09). "An Animal Model of a Behavioral Intervention for Depression". Neuron. 60 (1): 149–161. doi:10.1016/j.neuron.2008.07.041. ISSN   0896-6273. PMC   3417703 . PMID   18940595.
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