Yeka Aponte, Ph.D.

@article{SIEMIAN2020112912,
title = {Glutamatergic fast-spiking parvalbumin neurons in the lateral hypothalamus: Electrophysiological properties to behavior},
author = {Justin N Siemian and Sarah Sarsfield and Yeka Aponte},
url = {https://pubmed.ncbi.nlm.nih.gov/32289319/},
doi = {https://doi.org/10.1016/j.physbeh.2020.112912},
issn = {0031-9384},
year = {2020},
date = {2020-01-01},
journal = {Physiology & Behavior},
volume = {221},
pages = {112912},
abstract = {Throughout the central nervous system, neurons expressing the calcium-binding protein parvalbumin have been typically classified as GABAergic with fast-spiking characteristics. However, new methods that allow systematic characterization of the cytoarchitectural organization, connectivity, activity patterns, neurotransmitter nature, and function of genetically-distinct cell types have revealed populations of parvalbumin-positive neurons that are glutamatergic. Remarkably, such findings challenge longstanding concepts that fast-spiking neurons are exclusively GABAergic, suggesting conservation of the fast-spiking phenotype across at least two neurotransmitter systems. This review focuses on the recent advancements that have begun to reveal the functional roles of lateral hypothalamic parvalbumin-positive neurons in regulating behaviors essential for survival.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Siemian:2019aa,
title = {Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area.},
author = {Justin N Siemian and Cara B Borja and Sarah Sarsfield and Alexandre Kisner and Yeka Aponte},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31427712},
doi = {10.1038/s41598-019-48537-y},
issn = {2045-2322 (Electronic); 2045-2322 (Linking)},
year = {2019},
date = {2019-08-19},
journal = {Sci Rep},
volume = {9},
number = {1},
pages = {12026},
address = {Neuronal Circuits and Behavior Unit, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224-6823, USA.},
abstract = {A pivotal role of the lateral hypothalamus (LH) in regulating appetitive and reward-related behaviors has been evident for decades. However, the contributions of LH circuits to other survival behaviors have been less explored. Here we examine how lateral hypothalamic neurons that express the calcium-binding protein parvalbumin (PVALB; LH(PV) neurons), a small cluster of neurons within the LH glutamatergic circuitry, modulate nociception in mice. We find that photostimulation of LH(PV) neurons suppresses nociception to an acute, noxious thermal stimulus, whereas photoinhibition potentiates thermal nociception. Moreover, we demonstrate that LH(PV) axons form functional excitatory synapses on neurons in the ventrolateral periaqueductal gray (vlPAG), and photostimulation of these axons mediates antinociception to both thermal and chemical visceral noxious stimuli. Interestingly, this antinociceptive effect appears to occur independently of opioidergic mechanisms, as antagonism of mu-opioid receptors with systemically-administered naltrexone does not abolish the antinociception evoked by activation of this LH(PV)-->vlPAG pathway. This study directly implicates LH(PV) neurons in modulating nociception, thus expanding the repertoire of survival behaviors regulated by LH circuits.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Schiffino:2019aa,
title = {Activation of a lateral hypothalamic-ventral tegmental circuit gates motivation.},
author = {Felipe L Schiffino and Justin N Siemian and Michele Petrella and Brenton T Laing and Sarah Sarsfield and Cara B Borja and Anjali Gajendiran and Maria Laura Zuccoli and Yeka Aponte},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31291348/},
doi = {10.1371/journal.pone.0219522},
issn = {1932-6203 (Electronic); 1932-6203 (Linking)},
year = {2019},
date = {2019-07-10},
journal = {PLoS One},
volume = {14},
number = {7},
pages = {e0219522},
address = {National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, United States of America.},
abstract = {Across species, motivated states such as food-seeking and consumption are essential for survival. The lateral hypothalamus (LH) is known to play a fundamental role in regulating feeding and reward-related behaviors. However, the contributions of neuronal subpopulations in the LH have not been thoroughly identified. Here we examine how lateral hypothalamic leptin receptor-expressing (LHLEPR) neurons, a subset of GABAergic cells, regulate motivation in mice. We find that LHLEPR neuronal activation significantly increases progressive ratio (PR) performance, while inhibition decreases responding. Moreover, we mapped LHLEPR axonal projections and demonstrated that they target the ventral tegmental area (VTA), form functional inhibitory synapses with non-dopaminergic VTA neurons, and their activation promotes motivation for food. Finally, we find that LHLEPR neurons also regulate motivation to obtain water, suggesting that they may play a generalized role in motivation. Together, these results identify LHLEPR neurons as modulators within a hypothalamic-ventral tegmental circuit that gates motivation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Meng:2019aa,
title = {High-throughput synapse-resolving two-photon fluorescence microendoscopy for deep-brain volumetric imaging in vivo.},
author = {Guanghan Meng and Yajie Liang and Sarah Sarsfield and Wan-Chen Jiang and Rongwen Lu and Joshua Tate Dudman and Yeka Aponte and Na Ji},
url = {https://www.ncbi.nlm.nih.gov/pubmed/30604680/},
doi = {10.7554/eLife.40805},
issn = {2050-084X (Electronic); 2050-084X (Linking)},
year = {2019},
date = {2019-01-04},
journal = {Elife},
volume = {8},
address = {Department of Molecular and Cell Biology, University of California, Berkeley, United States.},
abstract = {Optical imaging has become a powerful tool for studying brains in vivo. The opacity of adult brains makes microendoscopy, with an optical probe such as a gradient index (GRIN) lens embedded into brain tissue to provide optical relay, the method of choice for imaging neurons and neural activity in deeply buried brain structures. Incorporating a Bessel focus scanning module into two-photon fluorescence microendoscopy, we extended the excitation focus axially and improved its lateral resolution. Scanning the Bessel focus in 2D, we imaged volumes of neurons at high-throughput while resolving fine structures such as synaptic terminals. We applied this approach to the volumetric anatomical imaging of dendritic spines and axonal boutons in the mouse hippocampus, and functional imaging of GABAergic neurons in the mouse lateral hypothalamus in vivo.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Kisner:2018aa,
title = {Electrophysiological properties and projections of lateral hypothalamic parvalbumin positive neurons.},
author = {Alexandre Kisner and Julia E Slocomb and Sarah Sarsfield and Maria Laura Zuccoli and Justin Siemian and Jay F Gupta and Arvind Kumar and Yeka Aponte},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29894514},
doi = {10.1371/journal.pone.0198991},
issn = {1932-6203 (Electronic); 1932-6203 (Linking)},
year = {2018},
date = {2018-06-12},
journal = {PLoS One},
volume = {13},
number = {6},
pages = {e0198991},
address = {Neuronal Circuits and Behavior Unit, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, United States of America.},
abstract = {Cracking the cytoarchitectural organization, activity patterns, and neurotransmitter nature of genetically-distinct cell types in the lateral hypothalamus (LH) is fundamental to develop a mechanistic understanding of how activity dynamics within this brain region are generated and operate together through synaptic connections to regulate circuit function. However, the precise mechanisms through which LH circuits orchestrate such dynamics have remained elusive due to the heterogeneity of the intermingled and functionally distinct cell types in this brain region. Here we reveal that a cell type in the mouse LH identified by the expression of the calcium-binding protein parvalbumin (PVALB; LHPV) is fast-spiking, releases the excitatory neurotransmitter glutamate, and sends long range projections throughout the brain. Thus, our findings challenge long-standing concepts that define neurons with a fast-spiking phenotype as exclusively GABAergic. Furthermore, we provide for the first time a detailed characterization of the electrophysiological properties of these neurons. Our work identifies LHPV neurons as a novel functional component within the LH glutamatergic circuitry.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Lagerlöf2016,
title = {The nutrient sensor OGT in PVN neurons regulates feeding.},
author = {Olof Lagerlöf and Julia E Slocomb and Ingie Hong and Yeka Aponte and Seth Blackshaw and Gerald W Hart and Richard L Huganir},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26989246},
doi = {10.1126/science.aad5494},
issn = {1095-9203 (Electronic); 0036-8075 (Linking)},
year = {2016},
date = {2016-03-18},
journal = {Science},
volume = {351},
number = {6279},
pages = {1293--1296},
address = {Solomon H. Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.},
abstract = {Maintaining energy homeostasis is crucial for the survival and health of organisms. The brain regulates feeding by responding to dietary factors and metabolic signals from peripheral organs. It is unclear how the brain interprets these signals. O-GlcNAc transferase (OGT) catalyzes the posttranslational modification of proteins by O-GlcNAc and is regulated by nutrient access. Here, we show that acute deletion of OGT from alphaCaMKII-positive neurons in adult mice caused obesity from overeating. The hyperphagia derived from the paraventricular nucleus (PVN) of the hypothalamus, where loss of OGT was associated with impaired satiety. These results identify O-GlcNAcylation in alphaCaMKII neurons of the PVN as an important molecular mechanism that regulates feeding behavior.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Bocarsly2015,
title = {Minimally invasive microendoscopy system for in vivo functional imaging of deep nuclei in the mouse brain.},
author = {Bocarsly, Miriam E and Jiang, Wan-Chen and Wang, Chen and Dudman, Joshua T and Ji, Na and Aponte, Yeka},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26601017},
doi = {10.1364/BOE.6.004546},
isbn = {2156-7085 (Print); 2156-7085 (Linking)},
year = {2015},
date = {2015-10-23},
journal = {Biomed Opt Express},
volume = {6},
number = {11},
pages = {4546--56},
abstract = {The ability to image neurons anywhere in the mammalian brain is a major goal of optical microscopy. Here we describe a minimally invasive microendoscopy system for studying the morphology and function of neurons at depth. Utilizing a guide cannula with an ultrathin wall, we demonstrated in vivo two-photon fluorescence imaging of deeply buried nuclei such as the striatum (2.5 mm depth), substantia nigra (4.4 mm depth) and lateral hypothalamus (5.0 mm depth) in mouse brain. We reported, for the first time, the observation of neuronal activity with subcellular resolution in the lateral hypothalamus and substantia nigra of head-fixed awake mice.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Aponte2011,
title = {AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training.},
author = {Yexica Aponte and Deniz Atasoy and Scott M Sternson},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21209617},
doi = {10.1038/nn.2739},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2011},
date = {2011-03-14},
journal = {Nat Neurosci},
volume = {14},
number = {3},
pages = {351--355},
address = {Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA.},
abstract = {Two intermingled hypothalamic neuron populations specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC) positively and negatively influence feeding behavior, respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type-specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron-mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Atasoy2008,
title = {A FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping.},
author = {Deniz Atasoy and Yexica Aponte and Helen Hong Su and Scott M Sternson},
url = {https://www.ncbi.nlm.nih.gov/pubmed/18614669},
doi = {10.1523/JNEUROSCI.1954-08.2008},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2008},
date = {2008-07-09},
journal = {J Neurosci},
volume = {28},
number = {28},
pages = {7025--7030},
address = {Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, USA.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Aponte2008,
title = {Efficient Ca2+ buffering in fast-spiking basket cells of rat hippocampus.},
author = {Yexica Aponte and Josef Bischofberger and Peter Jonas},
url = {https://www.ncbi.nlm.nih.gov/pubmed/18276734},
doi = {10.1113/jphysiol.2007.147298},
issn = {1469-7793 (Electronic); 0022-3751 (Linking)},
year = {2008},
date = {2008-04-15},
journal = {J Physiol},
volume = {586},
number = {8},
pages = {2061--2075},
address = {Physiological Institute I, University of Freiburg, Hermann-Herder-Str. 7, D-79104 Freiburg, Germany.},
abstract = {Fast-spiking parvalbumin-expressing basket cells (BCs) represent a major type of inhibitory interneuron in the hippocampus. These cells inhibit principal cells in a temporally precise manner and are involved in the generation of network oscillations. Although BCs show a unique expression profile of Ca(2+)-permeable receptors, Ca(2+)-binding proteins and Ca(2+)-dependent signalling molecules, physiological Ca(2+) signalling in these interneurons has not been investigated. To study action potential (AP)-induced dendritic Ca(2+) influx and buffering, we combined whole-cell patch-clamp recordings with ratiometric Ca(2+) imaging from the proximal apical dendrites of rigorously identified BCs in acute slices, using the high-affinity Ca(2+) indicator fura-2 or the low-affinity dye fura-FF. Single APs evoked dendritic Ca(2+) transients with small amplitude. Bursts of APs evoked Ca(2+) transients with amplitudes that increased linearly with AP number. Analysis of Ca(2+) transients under steady-state conditions with different fura-2 concentrations and during loading with 200 microm fura-2 indicated that the endogenous Ca(2+)-binding ratio was approximately 200 (kappa(S) = 202 +/- 26 for the loading experiments). The peak amplitude of the Ca(2+) transients measured directly with 100 microm fura-FF was 39 nm AP(-1). At approximately 23 degrees C, the decay time constant of the Ca(2+) transients was 390 ms, corresponding to an extrusion rate of approximately 600 s(-1). At 34 degrees C, the decay time constant was 203 ms and the corresponding extrusion rate was approximately 1100 s(-1). At both temperatures, continuous theta-burst activity with three to five APs per theta cycle, as occurs in vivo during exploration, led to a moderate increase in the global Ca(2+) concentration that was proportional to AP number, whereas more intense stimulation was required to reach micromolar Ca(2+) concentrations and to shift Ca(2+) signalling into a non-linear regime. In conclusion, dentate gyrus BCs show a high endogenous Ca(2+)-binding ratio, a small AP-induced dendritic Ca(2+) influx, and a relatively slow Ca(2+) extrusion. These specific buffering properties of BCs will sharpen the time course of local Ca(2+) signals, while prolonging the decay of global Ca(2+) signals.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Aponte2006,
title = {Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus.},
author = {Yexica Aponte and Cheng-Chang Lien and Ellen Reisinger and Peter Jonas},
url = {https://www.ncbi.nlm.nih.gov/pubmed/16690716},
doi = {10.1113/jphysiol.2005.104042},
issn = {0022-3751 (Print); 0022-3751 (Linking)},
year = {2006},
date = {2006-07-01},
journal = {J Physiol},
volume = {574},
number = {Pt 1},
pages = {229--243},
address = {Physiologisches Institut, Universitat Freiburg, Hermann-Herder-Str. 7, D-79104 Freiburg, Germany.},
abstract = {Hyperpolarization-activated channels (Ih or HCN channels) are widely expressed in principal neurons in the central nervous system. However, Ih in inhibitory GABAergic interneurons is less well characterized. We examined the functional properties of Ih in fast-spiking basket cells (BCs) of the dentate gyrus, using hippocampal slices from 17- to 21-day-old rats. Bath application of the Ih channel blocker ZD 7288 at a concentration of 30 microm induced a hyperpolarization of 5.7 +/- 1.5 mV, an increase in input resistance and a correlated increase in apparent membrane time constant. ZD 7288 blocked a hyperpolarization-activated current in a concentration-dependent manner (IC50, 1.4 microm). The effects of ZD 7288 were mimicked by external Cs+. The reversal potential of Ih was -27.4 mV, corresponding to a Na+ to K+ permeability ratio (PNa/PK) of 0.36. The midpoint potential of the activation curve of Ih was -83.9 mV, and the activation time constant at -120 mV was 190 ms. Single-cell expression analysis using reverse transcription followed by quantitative polymerase chain reaction revealed that BCs coexpress HCN1 and HCN2 subunit mRNA, suggesting the formation of heteromeric HCN1/2 channels. ZD 7288 increased the current threshold for evoking antidromic action potentials by extracellular stimulation, consistent with the expression of Ih in BC axons. Finally, ZD 7288 decreased the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal granule cells, the main target cells of BCs, to 70 +/- 4% of the control value. In contrast, the amplitude of mIPSCs was unchanged, consistent with the presence of Ih in inhibitory terminals. In conclusion, our results suggest that Ih channels are expressed in the somatodendritic region, axon and presynaptic elements of fast-spiking BCs in the hippocampus.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Tortorici2004,
title = {Involvement of cholecystokinin in the opioid tolerance induced by dipyrone (metamizol) microinjections into the periaqueductal gray matter of rats.},
author = {Victor Tortorici and Lourdes Nogueira and Yexica Aponte and Horacio Vanegas},
url = {https://www.ncbi.nlm.nih.gov/pubmed/15494191},
doi = {10.1016/j.pain.2004.08.006},
issn = {0304-3959 (Print); 0304-3959 (Linking)},
year = {2004},
date = {2004-11-01},
journal = {Pain},
volume = {112},
number = {1-2},
pages = {113--120},
address = {Instituto Venezolano de Investigaciones Cientificas (IVIC), Apartado 21827, Caracas 1020A, Venezuela. victort@cbb.ivic.ve},
abstract = {The analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs) is partly due to an action upon the periaqueductal gray matter (PAG), which triggers the descending pain control system and thus inhibits nociceptive transmission. This action of NSAIDs engages endogenous opioids at the PAG, the nucleus raphe magnus and the spinal cord. Repeated administration of NSAIDs such as dipyrone (metamizol) and acetylsalicylate thus induces tolerance to these compounds and cross-tolerance to morphine. Since cholecystokinin plays a key role in opioid tolerance, the present study in rats investigated whether PAG cholecystokinin is also responsible for tolerance to PAG-microinjected dipyrone. Microinjection of cholecystokinin (1 ng/0.5 microl) into PAG blocked the antinociceptive effect of a subsequent microinjection of dipyrone (150 microg/0.5 microl) into the same site, as evaluated by the tail flick and hot plate tests. Microinjection of proglumide (0.4 microg/0.5 microl), a non-selective cholecystokinin antagonist, into PAG prevented the development of tolerance to subsequent microinjections of dipyrone, as well as cross-tolerance to microinjection of morphine (5 microg/0.5 microl) into the same site. In rats tolerant to PAG dipyrone, a PAG microinjection of proglumide restored the antinociceptive effect of a subsequent microinjection of dipyrone or morphine. These results suggest that PAG-microinjected dipyrone triggers and/or potentiates local opioidergic circuits leading to descending inhibition of nociception, on the one hand, and to a local antiopioid action by cholecystokinin, on the other. Reiteration of these events would then result in an enhancement of cholecystokinin's antiopioid action and thus tolerance to opioids and dipyrone in the PAG.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}