Ali Deniz D. Güler

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Primary Appointment

Associate Professor, Biology

Education

  • BA, Bowdoin College
  • PhD, Biochemistry, Johns Hopkins School of Medicine

Research Disciplines

Neuroscience

Research Interests

Circadian entrainment for the treatment of metabolic and neurodegenerative diseases

Research Description

Biological processes ranging from gene transcription to behavior oscillate and are synchronized to the 24-hour day/night cycle. Mammalian circadian rhythms, orchestrated by the hypothalamic suprachiasmatic nucleus (SCN) allow appropriately timed physiological and behavioral responses to daily recurring external cues (i.e. sunrise or timed meal availability). The resulting synchrony of physiology to the astronomical day maximizes metabolic efficiency and good health. However, many of the stresses of modern society (i.e. artificial lighting and omnipresence of food) weaken and desynchronize circadian rhythms. This in turn increases the prevalence of many pathologies including metabolic disorders (i.e. obesity, type 2 diabetes and cardiovascular diseases), neurodegenerative diseases (i.e. Alzheimerâs and Parkinsonâs) and many types of cancer. The aim of my laboratory is to determine how circadian rhythms are synchronized (entrained) to external cues and how desynchronization impacts health. Although the neuronal pathways of light-driven entrainment are well-established, how other external cues, such as food availability, social interactions or exercise, influence the workings of the SCN remains unknown. In a recent breakthrough, we identified a neuronal connection between midbrain dopaminergic neurons that are activated in response to salient rewarding events and SCN neurons that express the dopamine receptor. We showed that this pathway accelerates entrainment and drives palatable food consumption outside of mealtimes. In parallel, we identified a novel molecular player that is necessary for anticipation of time-restricted food access. Now, we are leveraging our expertise in disentangling circadian entrainment neurocircuitry to determine whether strengthening circadian rhythmicity ameliorates symptoms of metabolic disorders or Alzheimerâs disease. Our work is aimed at understanding the relationship between entrainment cues, physiology and behavior while providing tangible strategies against the adverse consequences of circadian misalignment.

Personal Statement

My long-standing interest centers on how the central nervous system integrates both internal and external stimuli to generate a behavioral response. As a postdoctoral fellow in the laboratory of Dr. Samer Hattar (Johns Hopkins University), I identified the major pathway that carries environmental light information for non-image forming visual functions, including circadian photoentrainment and pupil constriction (Nature, 2008; PNAS, 2008; Nat. Neurosci. 2010). Next, in the laboratory of Dr. Richard Palmiter at University of Washington, I developed a transgenic model to modulate the activity of dopaminergic system and probe its role in a variety of behaviors including feeding (Nat. Commun., 2012; Cell Metab., 2015). In my own laboratory, we are uncovering how dopaminergic inputs to the circadian and energy balance circuits fine-tune physiological and behavioral responses (Curr. Bio., 2017 and 2020; eLife, 2020). To this end, we are developing and applying cutting-edge viral tracing strategies and in vivo neurotransmitter or electrophysiology measurement methodologies in awake and behaving mice. We perform these experiments in combination with optogenetic or chemogenetic actuators to classify specific cell groups or relevant neuronal connections (Curr. Bio., 2017 and 2020). Furthermore, we develop technologies to manipulate the behavioral responses predictably by activating the actuator proteins while the animals are freely behaving (Nat. Neurosci., 2016 and 2019).

Training

  • Predoctoral Training in Neuroscience

Selected Publications

2017

Denis, R. G. P., Joly-Amado, A., Webber, E., Langlet, F., Schaeffer, M., Padilla, S. L., . . . Luquet, S. (2017). Palatability Can Drive Feeding Independent of AgRP Neurons (vol 22, pg 646, 2015). CELL METABOLISM, 25(4), 975. doi:10.1016/j.cmet.2017.03.001

Moraes, M. N., Monteiro de Assis, L. V., Henriques, F. D. S., Batista, M. L. J., Guler, A. D., & de Lauro Castrucci, A. M. (2017). Cold-sensing TRPM8 channel participates in circadian control of the brown adipose tissue. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1864(12), 2415-2427. doi:10.1016/j.bbamcr.2017.09.011

Grippo, R. M., Purohit, A. M., Zhang, Q., Zweifel, L. S., & Guler, A. D. (2017). Direct Midbrain Dopamine Input to the Suprachiasmatic Nucleus Accelerates Circadian Entrainment. CURRENT BIOLOGY, 27(16), 2465-+. doi:10.1016/j.cub.2017.06.084

2016

Wheeler, M. A., Smith, C. J., Ottolini, M., Barker, B. S., Purohit, A. M., Grippo, R. M., . . . Guler, A. D. (2016). Genetically targeted magnetic control of the nervous system. NATURE NEUROSCIENCE, 19(5), 756-+. doi:10.1038/nn.4265

Warthen, D. M., Lambeth, P. S., Ottolini, M., Shi, Y., Barker, B. S., Gaykema, R. P., . . . Scott, M. M. (2016). Activation of Pyramidal Neurons in Mouse Medial Prefrontal Cortex Enhances Food-Seeking Behavior While Reducing Impulsivity in the Absence of an Effect on Food Intake. FRONTIERS IN BEHAVIORAL NEUROSCIENCE, 10. doi:10.3389/fnbeh.2016.00063

2015

Denis, R. G. P., Joly-Amado, A., Webber, E., Langlet, F., Schaeffer, M., Padilla, S. L., . . . Luquet, S. (2015). Palatability Can Drive Feeding Independent of AgRP Neurons. CELL METABOLISM, 22(4), 646-657. doi:10.1016/j.cmet.2015.07.011

Pang, Z., Sakamoto, T., Tiwari, V., Kim, Y. -S., Yang, F., Dong, X., . . . Caterina, M. J. (2015). Selective keratinocyte stimulation is sufficient to evoke nociception in mice. PAIN, 156(4), 656-665. doi:10.1097/j.pain.0000000000000092

Walker, M. T., Rupp, A., Elsaesser, R., Gueler, A. D., Sheng, W., Weng, S., . . . Montell, C. (2015). RdgB2 is required for dim-light input into intrinsically photosensitive retinal ganglion cells. MOLECULAR BIOLOGY OF THE CELL, 26(20), 3671-3678. doi:10.1091/mbc.E15-05-0288

2014

Suli, A., Guler, A. D., Raible, D. W., & Kimelman, D. (2014). A targeted gene expression system using the tryptophan repressor in zebrafish shows no silencing in subsequent generations. DEVELOPMENT, 141(5), 1167-1174. doi:10.1242/dev.100057

2013

Soden, M. E., Jones, G. L., Sanford, C. A., Chung, A. S., Gueler, A. D., Chavkin, C., . . . Zweifel, L. S. (2013). Disruption of Dopamine Neuron Activity Pattern Regulation through Selective Expression of a Human KCNN3 Mutation. NEURON, 80(4), 997-1009. doi:10.1016/j.neuron.2013.07.044

2012

Quintana, A., Sanz, E., Wang, W., Storey, G. P., Güler, A. D., Wanat, M. J., . . . Palmiter, R. D. (2012). Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors.. Nature neuroscience, 15(11), 1547-1555. doi:10.1038/nn.3239

Gueler, A. D., Rainwater, A., Parker, J. G., Jones, G. L., Argilli, E., Arenkiel, B. R., . . . Palmiter, R. D. (2012). Transient activation of specific neurons in mice by selective expression of the capsaicin receptor. NATURE COMMUNICATIONS, 3. doi:10.1038/ncomms1749

2010

Altimus, C. M., Gueler, A. D., Alam, N. M., Arman, A. C., Prusky, G. T., Sampath, A. P., & Hattar, S. (2010). Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities. NATURE NEUROSCIENCE, 13(9), 1107-U102. doi:10.1038/nn.2617

Lall, G. S., Revell, V. L., Momiji, H., Al Enezi, J., Altimus, C. M., Gueler, A. D., . . . Lucas, R. J. (2010). Distinct Contributions of Rod, Cone, and Melanopsin Photoreceptors to Encoding Irradiance. NEURON, 66(3), 417-428. doi:10.1016/j.neuron.2010.04.037