The goal of my research is
to understand, in health and disease, how brain circuits mediate responses to
sensory input. We study how brain circuits in sensory processing areas,
amygdala, hippocampus and cortex mediate behaviors such as associative learning.
We use an interdisciplinary approach employing advanced molecular biology,
animal genetics, bioinformatics, awake behaving recording with surgically
implanted tetrodes, modification of circuit processing by optogenetics and
generation of new devices and computational resources to understand brain
signal processing. My research involves studies in animal model systems and
humans. Importantly, my laboratory has substantial collaboration with engineers
following are highlights of accomplishments in the lab:
1. My early publications directly addressed what the role of Ca2+
is in the transduction pathway of olfactory sensory neurons (OSNs) of the main
olfactory epithelium. Using functional fluorescence microscopic imaging my
laboratory provided the first demonstration that odors elicit influx of Ca2+
into the OSNs mediated by opening of cAMP-gated (CNG) channels and recently
showed that Ca2+ influx into the sensory cilia takes place in
discrete microdomains. In addition, we showed that a subset of OSNs do not
express the Ca2+-activated Cl- channels thought to
depolarize cells after the CNG channel allows a ciliary influx of Ca2+.
In this subset of cells the increase of intraciliary Ca2+ elicits
opening of a ciliary Ca2+-gated transient receptor potential M5
(TRPM5) channel. Interestingly a substantial number of mitral cells innervating
glomeruli targeted by TRPM5-bearing OSNs in the main olfactory bulb innervate
the medial amygdala. This structure involved in sexual behavior was previously
thought to receive innervation only from the accessory olfactory bulb that
responds to pheromones and other semiochemicals. In addition, we showed that
this subset of TRPM5-bearing main olfactory epithelium OSNs responds at low
concentrations to semiochemicals such as MHC peptides and putative pheromones.
This is relevant to human olfaction because humans do not have a vomeronasal
organ, but do have a main olfactory epithelium.
a. Lopez F, Delgado R, Lopez R,
Bacigalupo J, Restrepo D. Transduction for Pheromones in the Main Olfactory
Epithelium Is Mediated by the Ca2+-Activated Channel TRPM5. J Neurosci.
2014;34(9):3268-78. Epub 2014/02/28. doi: 10.1523/JNEUROSCI.4903-13.2014.
PubMed PMID: 24573286; PubMed Central PMCID: PMC3935088.
b. Gonzalez-Silva C, Vera J, Bono MR,
Gonzalez-Billault C, Baxter B, Hansen A, et al. Ca2+-activated Cl- channels of
the ClCa family express in the cilia of a subset of rat olfactory sensory neurons.
PLoS One. 2013;8(7):e69295. Epub 2013/07/23. doi: 10.1371/journal.pone.0069295.
PubMed PMID: 23874937; PubMed Central PMCID: PMC3706372.
c. Restrepo D, Miyamoto T, Bryant BP, Teeter
JH. Odor stimuli trigger influx of calcium into olfactory neurons of the
channel catfish. Science. 1990;249(4973):1166-8. Epub 1990/09/07. PubMed PMID:
d. Thompson JA, Salcedo E, Restrepo D, Finger
TE. Second-order input to the medial amygdala from olfactory sensory neurons
expressing the transduction channel TRPM5. J Comp Neurol. 2012;520(8):1819-30.
doi: 10.1002/cne.23015. PubMed PMID: 22120520; PubMed Central PMCID:
My laboratory pioneered recording of odor Ca2+ responses in
isolated human OSNs obtained by biopsy of the olfactory epithelium and used
this technique and human neuronal cell culture to study olfactory transduction
as well as olfactory function in the elderly, anosmics, olfactory neuroblastoma
and depressed patients. We found that the human OSNs respond to odors more
specifically than rodent OSNs. In addition we found that OSNs respond
differently to odors in unmedicated depressed patients compared to controls.
Finally, we showed that, while OSNs respond specifically to odors in adult
human OSNs (<45 years old), OSNs from older individuals (>65 years old)
respond to multiple odors suggesting that in the elderly these neurons are less
selective, perhaps by expressing multiple olfactory receptors per cell leading
to an “olfactory white” response that mediates the decrease in odor sensitivity
in the elderly.
a. Rawson NE, Gomez G, Cowart BJ, Kriete A, Pribitkin E, Restrepo D.
Age-associated loss of selectivity in human olfactory sensory neurons.
Neurobiol Aging. 2012;33:1913-9. Epub 2011/11/15. doi: 10.1016/j.neurobiolaging.2011.09.036.
PubMed PMID: 22074806; PubMed Central PMCID: PMC3299952.
CG, Gomez G, Restrepo D, Friedman E, Josiassen R, Pribitkin EA, et al. Aberrant
intracellular calcium signaling in olfactory neurons from patients with bipolar
disorder. Am J Psychiatry. 2005;162(3):616-8. Epub 2005/03/03. doi: 162/3/616
[pii] 10.1176/appi.ajp.162.3.616. PubMed PMID: 15741484.
c. Restrepo D, Okada Y, Teeter JH, Lowry LD,
Cowart B, Brand JG. Human olfactory neurons respond to odor stimuli with an
increase in cytoplasmic Ca2+. Biophys J. 1993;64(6):1961-6. Epub 1993/06/01.
doi: S0006-3495(93)81565-0 [pii] 10.1016/S0006-3495(93)81565-0. PubMed PMID:
8369416; PubMed Central PMCID: PMC1262528.
Rawson NE, Gomez G, Cowart B, Brand JG, Lowry LD, Pribitkin EA, et al.
Selectivity and response characteristics of human olfactory neurons. J
Neurophysiol. 1997;77(3):1606-13. Epub 1997/03/01. PubMed PMID: 9084623.
Ours was among
the first laboratories performing recordings in the olfactory bulb, piriform
cortex and other olfactory brain areas in awake behaving mice. We made the
surprising finding that the spike rate of mitral cells responds to whether the
odor is rewarded (odor value), not to the odor identity. Subsequently we have
found that the gamma frequency spike-field coherence responds to an odor
feature consistent with odor identity. Finally, we have used optogenetics to
show that mice can differentiate between pulses of glomerular input that differ
by 10 msec in duration. These studies demonstrate that the olfactory system
functions in a very different manner in the awake behaving animal compared to
the anesthetized animal or to the circuit in brain slice preparations. This
implies that in order to understand function of this circuit in the awake
behaving animal it is key to understand modulation and centrifugal feedback to
the olfactory bulb.
a. Li A, Gire DH, Restrepo D. Υ
spike-field coherence in a population of olfactory bulb neurons differentiates
between odors irrespective of associated outcome J Neurosci. 35(14):5808-22.
doi: 10.1523/JNEUROSCI.4003-14.2015. PubMed PMID: 25855190, 2015.
b. Li A, Gire DH, Bozza T, Restrepo D. Precise
detection of direct glomerular input duration by the olfactory bulb. JNeurosci.
2014;34:16058-64. doi: 10.1523/JNEUROSCI.3382-14.2014.
c. Gire DH, Whitesell JD, Doucette W, Restrepo D.
Information for decision-making and stimulus identification is multiplexed in
sensory cortex. Nat Neurosci. 2013;16:991-3. Epub 2013/06/25. doi:
10.1038/nn.3432. PubMed PMID: 23792942.
d. Doucette W, Gire DH, Whitesell J, Carmean V,
Lucero MT, Restrepo D. Associative Cortex Features in the First Olfactory Brain
Relay Station. Neuron. 2011;69:1176-87. Epub 3/24/2011.
4. We have collaborated with engineers in developing novel techniques for
studying brain function. With help of Dr. Stefan Hell, winner of the 2014 Nobel
prize in chemistry, Dr. Emily Gibson and I developed a STED nanoscope that is
used as a core for high resolution imaging in biological samples in our campus.
Furthermore, we developed shape memory polymer-based electrodes that would slowly self-implant
compliant conductors into the brain, and both decrease initial trauma resulting
from implantation and enhance long-term biocompatibility for long-term neuronal
measurement and stimulation in brain tissue.
In addition, in order to understand the
constraints of inserting probes in brain tissue we performed a study of micrometer-scale penetration mechanics and
material properties of mouse brain tissue in vivo. Finally in a
collaboration with engineers and physicists we have developed a novel
electrowetting fiber coupled microscope that will allow future imaging and
optogenetic modulation of neuronal activity deep in brain tissue. These
techniques are designed to provide novel tools for studying and modifying brain
a. Sharp AA, Panchawagh HV, Ortega A,
Artale R, Richardson-Burns S, Finch DS, et al. Toward a self-deploying shape
memory polymer neuronal electrode. J Neural Eng. 2006;3(4):L23-30. Epub
2006/11/25. doi: S1741-2560(06)33474-X [pii] 10.1088/1741-2560/3/4/L02. PubMed
b. Lin W, Margolskee R, Donnert G, Hell SW,
Restrepo D. Olfactory neurons expressing transient receptor potential channel
M5 (TRPM5) are involved in sensing semiochemicals. Proc Natl Acad Sci U S A.
2007;104(7):2471-6. Epub 2007/02/03. doi: 0610201104 [pii]
10.1073/pnas.0610201104. PubMed PMID: 17267604; PubMed Central PMCID: PMC1892929.
c. Meyer SA,
Ozbay, B., Restrepo, D., Gibson, E.A. Super-resolution imaging of ciliary
microdomains in isolated olfactory sensory neurons using a custom STED
microscope. Proc SPIE. 2014;8950, Single Molecule Spectroscopy and
Superresolution Imaging VII, 89500W (March 4, 2014). doi:
Zane, R., Popovic, Z., Sharp, A. and Restrepo, D. 2009. Systems and methods for
receiving and managing power in wireless devices. US Patent No. 7,956,572.