Position
Chief,
Neuronal Circuits and Behavior Unit
Associate Director,
Diversity and Inclusion
Assistant Professor,
Johns Hopkins University Neuroscience
Contact
Biomedical Research Center251 Bayview Boulevard
Suite 200
Room 07A707
Baltimore, MD 21224
Phone: 443-740-2690
Email: yeka.aponte@nih.gov
Education
Post-doctoral Training - Janelia Farm Research Campus of the Howard Hughes Medical Institute, Ashburn, VA (Adviser: Dr. Scott Sternson)
Ph.D. - Natural Sciences, University of Freiburg, Germany (Adviser: Prof. Dr. Peter Jonas)
Background
Dr. Aponte received her Ph.D. from the University of Freiburg. Working with Prof. Dr. Peter Jonas she studied the functional properties of hyperpolarization-activated cation channels and dendritic calcium dynamics in fast-spiking hippocampal interneurons. During her postdoctoral work with Dr. Scott Sternson at the Janelia Farm Research Campus of the Howard Hughes Medical Institute (JFRC/HHMI), she studied neuronal circuits controlling feeding behaviors using optogenetic techniques in awake, behaving mice. She also applied in vivo electrophysiological methods to molecularly-defined neuron populations. She joined the NIDA/IRP as an Earl Stadtman Tenure-Track Investigator and her laboratory uses a combination of optogenetics, chemogenetics, electrophysiology, two- and single-photon fluorescence endomicroscopy, and behavioral assays to elucidate the neuronal mechanisms regulating the rewarding nature of food intake and drug abuse.
Research Interests
Our interest is to understand how genetically-identified cell types and their projections drive behaviors essential for survival. Using the mouse as our model system, we apply optogenetics and chemogenetics to manipulate neuronal circuits in awake, behaving mice. In addition, we use a combination of electrophysiology, two- and single-photon fluorescence endomicroscopy, and behavioral assays to elucidate the neuronal basis of survival behaviors (i.e. feeding and pain) and to determine how these neuronal circuits drive the rewarding and addictive nature of food and opioids. Public awareness of the addictive properties of food and opioids has been growing progressively throughout the last decade. Both addiction and overeating are disorders by which individuals learn rewarding associations between stimuli such as drugs of abuse and highly palatable food. Therefore, our laboratory is interested in understanding the addictive aspects of both feeding and drug abuse behaviors. We study this topic at the level of neuronal circuits in the context of behaviors, cell types, and synaptic connectivity. Neuronal circuits are composed of diverse collections of cell types, each having a distinct set of synaptic connections and performing specific functions. To understand how neuronal circuits drive behaviors, it is essential to examine the function of specific cell types in the circuit. However, studies have been mostly unable to identify the cell types involved in specific behaviors. Furthermore, experiments to date have largely been unable to determine when specific cell types are active to provide quantitative relationships between circuit activity and behavior. Ultimately, understanding the mechanisms regulating food intake and the rewarding and addictive nature of food will enhance our ability to battle disorders such as obesity, diabetes, anorexia, bulimia, and addiction.
Publications
Selected Publications
2021
Siemian, Justin N; Arenivar, Miguel A; Sarsfield, Sarah; Aponte, Yeka
Hypothalamic control of interoceptive hunger Journal Article
In: Curr Biol, 31 (17), pp. 3797–3809.e5, 2021, ISSN: 1879-0445.
@article{pmid34273280,
title = {Hypothalamic control of interoceptive hunger},
author = {Justin N Siemian and Miguel A Arenivar and Sarah Sarsfield and Yeka Aponte},
url = {https://pubmed.ncbi.nlm.nih.gov/34273280/},
doi = {10.1016/j.cub.2021.06.048},
issn = {1879-0445},
year = {2021},
date = {2021-09-01},
urldate = {2021-09-01},
journal = {Curr Biol},
volume = {31},
number = {17},
pages = {3797--3809.e5},
abstract = {While energy balance is critical to survival, many factors influence food intake beyond caloric need or "hunger." Despite this, some neurons that drive feeding in mice are routinely referred to as "hunger neurons," whereas others are not. To understand how specific hypothalamic circuits control interoceptive hunger, we trained mice to discriminate fasted from sated periods. We then manipulated three hypothalamic neuronal populations with well-known effects on feeding while mice performed this task. While activation of ARC neurons in sated mice caused mice to report being food-restricted, LH neuron activation or LH neuron inhibition did not. In contrast, LH neuron inhibition or LH neuron activation in fasted mice attenuated natural hunger, whereas ARC neuron inhibition did not. Each neuronal population evoked distinct effects on food consumption and reward. After satiety- or sickness-induced devaluation, ARC neurons drove calorie-specific feeding, while LH neurons drove calorie-indiscriminate food intake. Our data support a role for ARC neurons in homeostatic feeding and implicate them in driving a hunger-like internal state that directs behavior toward caloric food sources. Moreover, manipulations of LH circuits did not evoke hunger-like effects in sated mice, suggesting that they may govern feeding more related to reward, compulsion, or generalized consumption than to energy balance, but also that these LH circuits can be powerful negative appetite modulators in fasted mice. This study highlights the complexity of hypothalamic feeding regulation and can be used as a framework to characterize how other neuronal circuits affect hunger and identify potential therapeutic targets for eating disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
While energy balance is critical to survival, many factors influence food intake beyond caloric need or "hunger." Despite this, some neurons that drive feeding in mice are routinely referred to as "hunger neurons," whereas others are not. To understand how specific hypothalamic circuits control interoceptive hunger, we trained mice to discriminate fasted from sated periods. We then manipulated three hypothalamic neuronal populations with well-known effects on feeding while mice performed this task. While activation of ARC neurons in sated mice caused mice to report being food-restricted, LH neuron activation or LH neuron inhibition did not. In contrast, LH neuron inhibition or LH neuron activation in fasted mice attenuated natural hunger, whereas ARC neuron inhibition did not. Each neuronal population evoked distinct effects on food consumption and reward. After satiety- or sickness-induced devaluation, ARC neurons drove calorie-specific feeding, while LH neurons drove calorie-indiscriminate food intake. Our data support a role for ARC neurons in homeostatic feeding and implicate them in driving a hunger-like internal state that directs behavior toward caloric food sources. Moreover, manipulations of LH circuits did not evoke hunger-like effects in sated mice, suggesting that they may govern feeding more related to reward, compulsion, or generalized consumption than to energy balance, but also that these LH circuits can be powerful negative appetite modulators in fasted mice. This study highlights the complexity of hypothalamic feeding regulation and can be used as a framework to characterize how other neuronal circuits affect hunger and identify potential therapeutic targets for eating disorders.
Siemian, Justin N; Arenivar, Miguel A; Sarsfield, Sarah; Borja, Cara B; Russell, Charity N; Aponte, Yeka
Lateral hypothalamic LEPR neurons drive appetitive but not consummatory behaviors Journal Article
In: Cell Rep, 36 (8), pp. 109615, 2021, ISSN: 2211-1247.
@article{pmid34433027,
title = {Lateral hypothalamic LEPR neurons drive appetitive but not consummatory behaviors},
author = {Justin N Siemian and Miguel A Arenivar and Sarah Sarsfield and Cara B Borja and Charity N Russell and Yeka Aponte},
url = {https://pubmed.ncbi.nlm.nih.gov/34433027/},
doi = {10.1016/j.celrep.2021.109615},
issn = {2211-1247},
year = {2021},
date = {2021-08-01},
urldate = {2021-08-01},
journal = {Cell Rep},
volume = {36},
number = {8},
pages = {109615},
abstract = {Assigning behavioral roles to genetically defined neurons within the lateral hypothalamus (LH) is an ongoing challenge. We demonstrate that a subpopulation of LH GABAergic neurons expressing leptin receptors (LH) specifically drives appetitive behaviors in mice. Ablation of LH GABAergic neurons (LH) decreases weight gain and food intake, whereas LH ablation does not. Appetitive learning in a Pavlovian conditioning paradigm is delayed in LH-ablated mice but prevented entirely in LH-ablated mice. Both LH and LH neurons bidirectionally modulate reward-related behaviors, but only LH neurons affect feeding. In the Pavlovian paradigm, only LH activity discriminates between conditioned cues. Optogenetic activation or inhibition of either population in this task disrupts discrimination. However, manipulations of LH→VTA projections evoke divergent effects on responding. Unlike food-oriented learning, chemogenetic inhibition of LH neurons does not alter cocaine-conditioned place preference but attenuates cocaine sensitization. Thus, LH neurons may specifically regulate appetitive behaviors toward non-drug reinforcers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Assigning behavioral roles to genetically defined neurons within the lateral hypothalamus (LH) is an ongoing challenge. We demonstrate that a subpopulation of LH GABAergic neurons expressing leptin receptors (LH) specifically drives appetitive behaviors in mice. Ablation of LH GABAergic neurons (LH) decreases weight gain and food intake, whereas LH ablation does not. Appetitive learning in a Pavlovian conditioning paradigm is delayed in LH-ablated mice but prevented entirely in LH-ablated mice. Both LH and LH neurons bidirectionally modulate reward-related behaviors, but only LH neurons affect feeding. In the Pavlovian paradigm, only LH activity discriminates between conditioned cues. Optogenetic activation or inhibition of either population in this task disrupts discrimination. However, manipulations of LH→VTA projections evoke divergent effects on responding. Unlike food-oriented learning, chemogenetic inhibition of LH neurons does not alter cocaine-conditioned place preference but attenuates cocaine sensitization. Thus, LH neurons may specifically regulate appetitive behaviors toward non-drug reinforcers.
Siemian, Justin N; Arenivar, Miguel A; Sarsfield, Sarah; Borja, Cara B; Erbaugh, Lydia J; Eagle, Andrew L; Robison, Alfred J; Leinninger, Gina; Aponte, Yeka
An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice Journal Article
In: eLife, 10 , pp. e66446, 2021, ISSN: 2050-084X.
@article{10.7554/eLife.66446,
title = {An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice},
author = {Justin N Siemian and Miguel A Arenivar and Sarah Sarsfield and Cara B Borja and Lydia J Erbaugh and Andrew L Eagle and Alfred J Robison and Gina Leinninger and Yeka Aponte},
editor = {Peggy Mason and Michael Taffe and Robert Gereau and Peggy Mason and Alexander C Jackson and Gregory Corder and Asaf Keller},
url = {https://pubmed.ncbi.nlm.nih.gov/34042586/},
doi = {10.7554/eLife.66446},
issn = {2050-084X},
year = {2021},
date = {2021-05-01},
journal = {eLife},
volume = {10},
pages = {e66446},
publisher = {eLife Sciences Publications, Ltd},
abstract = {Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHtextsuperscriptPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHtextsuperscriptPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHtextsuperscriptPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHtextsuperscriptPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHtextsuperscriptPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHtextsuperscriptPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHtextsuperscriptPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHtextsuperscriptPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHtextsuperscriptPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHtextsuperscriptPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHtextsuperscriptPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHtextsuperscriptPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.
Laing, Brenton T; Siemian, Justin N; Sarsfield, Sarah; Aponte, Yeka
Fluorescence microendoscopy for in vivo deep-brain imaging of neuronal circuits Journal Article
In: Journal of Neuroscience Methods, 348 , pp. 109015, 2021, ISSN: 0165-0270.
@article{LAING2021109015,
title = {Fluorescence microendoscopy for in vivo deep-brain imaging of neuronal circuits},
author = {Brenton T Laing and Justin N Siemian and Sarah Sarsfield and Yeka Aponte},
url = {https://pubmed.ncbi.nlm.nih.gov/33259847/},
doi = {https://doi.org/10.1016/j.jneumeth.2020.109015},
issn = {0165-0270},
year = {2021},
date = {2021-01-01},
journal = {Journal of Neuroscience Methods},
volume = {348},
pages = {109015},
abstract = {Imaging neuronal activity in awake, behaving animals has become a groundbreaking method in neuroscience that has rapidly enhanced our understanding of how the brain works. In vivo microendoscopic imaging has enabled researchers to see inside the brains of experimental animals and thus has emerged as a technology fit to answer many experimental questions. By combining microendoscopy with cutting edge targeting strategies and sophisticated analysis tools, neuronal activity patterns that underlie changes in behavior and physiology can be identified. However, new users may find it challenging to understand the techniques and to leverage this technology to best suit their needs. Here we present a background and overview of the necessary components for performing in vivo optical calcium imaging and offer some detailed guidance for current recommended approaches.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Imaging neuronal activity in awake, behaving animals has become a groundbreaking method in neuroscience that has rapidly enhanced our understanding of how the brain works. In vivo microendoscopic imaging has enabled researchers to see inside the brains of experimental animals and thus has emerged as a technology fit to answer many experimental questions. By combining microendoscopy with cutting edge targeting strategies and sophisticated analysis tools, neuronal activity patterns that underlie changes in behavior and physiology can be identified. However, new users may find it challenging to understand the techniques and to leverage this technology to best suit their needs. Here we present a background and overview of the necessary components for performing in vivo optical calcium imaging and offer some detailed guidance for current recommended approaches.
2020
Siemian, Justin N; Sarsfield, Sarah; Aponte, Yeka
Glutamatergic fast-spiking parvalbumin neurons in the lateral hypothalamus: Electrophysiological properties to behavior Journal Article
In: Physiology & Behavior, 221 , pp. 112912, 2020, ISSN: 0031-9384.
@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}
}
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.
2019
Siemian, Justin N; Borja, Cara B; Sarsfield, Sarah; Kisner, Alexandre; Aponte, Yeka
Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area. Journal Article
In: Sci Rep, 9 (1), pp. 12026, 2019, ISSN: 2045-2322 (Electronic); 2045-2322 (Linking).
@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}
}
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.
Schiffino, Felipe L; Siemian, Justin N; Petrella, Michele; Laing, Brenton T; Sarsfield, Sarah; Borja, Cara B; Gajendiran, Anjali; Zuccoli, Maria Laura; Aponte, Yeka
Activation of a lateral hypothalamic-ventral tegmental circuit gates motivation. Journal Article
In: PLoS One, 14 (7), pp. e0219522, 2019, ISSN: 1932-6203 (Electronic); 1932-6203 (Linking).
@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}
}
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.
Meng, Guanghan; Liang, Yajie; Sarsfield, Sarah; Jiang, Wan-Chen; Lu, Rongwen; Dudman, Joshua Tate; Aponte, Yeka; Ji, Na
High-throughput synapse-resolving two-photon fluorescence microendoscopy for deep-brain volumetric imaging in vivo. Journal Article
In: Elife, 8 , 2019, ISSN: 2050-084X (Electronic); 2050-084X (Linking).
@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}
}
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.
2018
Kisner, Alexandre; Slocomb, Julia E; Sarsfield, Sarah; Zuccoli, Maria Laura; Siemian, Justin; Gupta, Jay F; Kumar, Arvind; Aponte, Yeka
Electrophysiological properties and projections of lateral hypothalamic parvalbumin positive neurons. Journal Article
In: PLoS One, 13 (6), pp. e0198991, 2018, ISSN: 1932-6203 (Electronic); 1932-6203 (Linking).
@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}
}
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.
2016
Lagerlöf, Olof; Slocomb, Julia E; Hong, Ingie; Aponte, Yeka; Blackshaw, Seth; Hart, Gerald W; Huganir, Richard L
The nutrient sensor OGT in PVN neurons regulates feeding. Journal Article
In: Science, 351 (6279), pp. 1293–1296, 2016, ISSN: 1095-9203 (Electronic); 0036-8075 (Linking).
@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}
}
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.
2015
Bocarsly, Miriam E; Jiang, Wan-Chen; Wang, Chen; Dudman, Joshua T; Ji, Na; Aponte, Yeka
Minimally invasive microendoscopy system for in vivo functional imaging of deep nuclei in the mouse brain. Journal Article
In: Biomed Opt Express, 6 (11), pp. 4546–56, 2015, ISBN: 2156-7085 (Print); 2156-7085 (Linking).
@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}
}
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.
2011
Aponte, Yexica; Atasoy, Deniz; Sternson, Scott M
AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Journal Article
In: Nat Neurosci, 14 (3), pp. 351–355, 2011, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@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}
}
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.
2008
Atasoy, Deniz; Aponte, Yexica; Su, Helen Hong; Sternson, Scott M
A FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. Journal Article
In: J Neurosci, 28 (28), pp. 7025–7030, 2008, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@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}
}
Aponte, Yexica; Bischofberger, Josef; Jonas, Peter
Efficient Ca2+ buffering in fast-spiking basket cells of rat hippocampus. Journal Article
In: J Physiol, 586 (8), pp. 2061–2075, 2008, ISSN: 1469-7793 (Electronic); 0022-3751 (Linking).
@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}
}
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.
2006
Aponte, Yexica; Lien, Cheng-Chang; Reisinger, Ellen; Jonas, Peter
Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus. Journal Article
In: J Physiol, 574 (Pt 1), pp. 229–243, 2006, ISSN: 0022-3751 (Print); 0022-3751 (Linking).
@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}
}
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.
2004
Tortorici, Victor; Nogueira, Lourdes; Aponte, Yexica; Vanegas, Horacio
In: Pain, 112 (1-2), pp. 113–120, 2004, ISSN: 0304-3959 (Print); 0304-3959 (Linking).
@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}
}
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.
