Mariella De Biasi - Academia.edu (original) (raw)
Papers by Mariella De Biasi
CARS imaging of ex vivo ovarian cancer samples
CARS imaging of ex vivo ovarian cancer samples
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling... more Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/ Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. Ó2018 AACR.
eLife, Mar 15, 2022
Sensory systems must account for both contextual factors and prior experience to adaptively engag... more Sensory systems must account for both contextual factors and prior experience to adaptively engage with the dynamic external environment. In the central auditory system, neurons modulate their responses to sounds based on statistical context. These response modulations can be understood through a hierarchical predictive coding lens: responses to repeated stimuli are progressively decreased, in a process known as repetition suppression, whereas unexpected stimuli produce a prediction error signal. Prediction error incrementally increases along the auditory hierarchy from the inferior colliculus (IC) to the auditory cortex (AC), suggesting that these regions may engage in hierarchical predictive coding. A potential substrate for top-down predictive cues is the massive set of descending projections from the AC to subcortical structures, although the role of this system in predictive processing has never been directly assessed. We tested the effect of optogenetic inactivation of the auditory cortico-collicular feedback in awake mice on responses of IC neurons to stimuli designed to test prediction error and repetition suppression. Inactivation of the cortico-collicular pathway led to a decrease in prediction error in IC. Repetition suppression was unaffected by cortico-collicular inactivation, suggesting that this metric may reflect fatigue of bottom-up sensory inputs rather than predictive processing. We also discovered populations of IC units that exhibit repetition enhancement, a sequential increase in firing with stimulus repetition. Cortico-collicular inactivation led to a decrease in repetition enhancement in the central nucleus of IC, suggesting that it is a top-down phenomenon. Negative prediction error, a stronger response to a tone in a predictable rather than unpredictable sequence, was suppressed in shell IC units during cortico-collicular inactivation. These changes in predictive coding metrics arose from bidirectional modulations in the response to the standard and deviant contexts, such that the units in IC responded more similarly to each context in the absence of cortical input. We also investigated how these metrics compare between the anesthetized and awake states by recording from the same units under both conditions. We found that metrics of predictive coding and deviance detection differ depending on the anesthetic state of the animal, with negative prediction error emerging in the central IC and repetition enhancement and prediction error being more prevalent in the absence of anesthesia. Overall, our results demonstrate that the AC provides cues about the statistical context of sound to subcortical brain regions via direct feedback, regulating processing of both prediction and repetition.
The FASEB Journal, Aug 25, 2010
α6* (asterisk indicates the presence of additional subunits) nicotinic acetylcholine receptors (n... more α6* (asterisk indicates the presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) are broadly implicated in catecholamine‐dependent disorders that involve attention, motor movement, and nicotine self‐administration. Different molecular forms of 06 nAChRs mediate catechol‐amine release, but receptor differentiation is greatly hampered by a paucity of subtype selective ligands. 0‐Conotoxins are nAChR‐targeted peptides used by Conus species to incapacitate prey. We hypothesized that distinct conotoxin‐binding kinetics could be exploited to develop a series of selective probes to enable study of native receptor subtypes. Proline6 of 0‐conotoxin BuIA was found to be critical for nAChR selectivity; substitution of proline6 with 4‐hydroyx‐proline increased the IC50 by 2800‐fold at 06/o3β2β3 but only by 6‐fold at o6/o3β4 nAChRs (to 1300 and 12 nM, respectively). We used conotoxin probes together with subunit‐null mice to interrogate nAChR subtypes that modulate hippocampal norepi‐nephrine release. Release was abolished in 06‐null mutant mice. 0‐Conotoxin BuIA[T5A;P6O] partially blocked norepinephrine release in wild‐type controls but failed to block release in β4_/_ mice. In contrast, BuIA[T5A;P6O] failed to block dopamine release in the wild‐type striatum known to contain o6β2* nAChRs. BuIA[T5A;P6O] is a novel ligand for distinguishing between closely related 06* nAChRs; o6β4* nAChRs modulate norepinephrine release in hippocampus but not dopamine release in stria‐tum.—Azam, L., Maskos, U., Changeux, J.‐P., Dow‐ell, C. D., Christensen, S., De Biasi, M., McIntosh, J. M. o‐Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between o6β4 and o6β2 nAChRs and blocks nicotine‐stimulated norepinephrine release. FASEBJ. 24, 5113–5123 (2010). www.fasebj.org
Neuropharmacology, Sep 1, 2022
bioRxiv (Cold Spring Harbor Laboratory), Oct 21, 2022
Nicotine is an addictive drug whose popularity has recently increased, particularly among adolesc... more Nicotine is an addictive drug whose popularity has recently increased, particularly among adolescents, due to the availability of electronic nicotine devices (i.e., "vaping") and nicotine eliquids containing additives with rich chemosensory properties. Some efforts to understand the role of these additives in nicotine reward suggest that they increase nicotine reward and reinforcement, but the sensory contributions of additives, especially in their vapor forms, are largely untested. Here, to better understand how a fruit-flavored (i.e., strawberry) additive influences nicotine reward and aversion, we used a conditioned place preference (CPP) procedure in which nicotine and a strawberry additive were delivered as a vapor to male and female adolescent mice. We found that nicotine vapor alone can lead to dose-dependent CPP when using a biased design. The strawberry additive did not produce CPP on its own, and we did not observe an effect of the strawberry additive on nicotine vapor-induced reward. Nevertheless, mice exposed to nicotine + strawberry additive vapor had higher plasma cotinine concentrations,. CC-BY-NC-ND 4.
bioRxiv (Cold Spring Harbor Laboratory), Apr 26, 2021
Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide... more Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide. Topiramate (TPM) is an antiepileptic drug that has been shown to reduce ethanol drinking in humans. However, TPM is associated with a variety of adverse effects due to its interaction with many receptor systems and intracellular pathways. Thus, a better understanding of the role of TPM's main molecular targets in AUD could yield better therapeutic tools. GluK1-containing kainate receptors (GluK1*KARs) are non-selectively inhibited by TPM, and genetic association studies suggest that this receptor system could be targeted to reduce drinking in AUD patients. We examined the efficacy of LY466195, a selective inhibitor of GluK1*KAR, in reducing ethanol consumption in the intermittent two-bottle choice paradigm in mice. The effect of LY466195 on various ethanol-related phenotypes was investigated by quantification of alcohol intake, physical signs of withdrawal, conditioned place preference (CPP) and in vivo microdialysis in the nucleus accumbens. Selective GluK1*KAR inhibition reduced ethanol intake and preference in a dosedependent manner. LY466195 treatment attenuated the physical manifestations of ethanol withdrawal and influenced the rewarding properties of ethanol. Interestingly, LY466195 injection also normalized changes in dopamine levels in response to acute ethanol in ethanol-dependent mice, but had no effect in ethanol-naïve mice, suggesting ethanol state-dependent effects. The data point to GluK1*KARs as an attractive pharmacological target for the treatment of AUD.
Neuropharmacology, Oct 1, 2020
The popularity of e-cigarettes has skyrocketed in recent years, and most vapers use flavored e-ci... more The popularity of e-cigarettes has skyrocketed in recent years, and most vapers use flavored e-cigarette products. Consumption of flavored e-cigarettes exceeds that of combustible cigarettes and other tobacco products among adolescents, who are particularly vulnerable to becoming nicotine dependent. Flavorings have been used by the tobacco industry since the 17th century, but the use of flavors by the e-cigarette industry to create products with “characterizing” flavors (i.e. flavors other than tobacco or menthol) has sparked a public health debate. This review addresses the possibility that characterizing flavors make nicotine more appealing, rewarding and addictive. It also discusses ways in which preclinical and clinical studies could improve our understanding of the mechanisms by which flavors may alter nicotine reward and reinforcement.This article is part of the special issue on ‘Contemporary Advances in Nicotine Neuropharmacology’.
Journal of Addiction Research and Therapy, 2012
Tobacco use is a major health problem, and nicotine is the main addictive component. Nicotine bin... more Tobacco use is a major health problem, and nicotine is the main addictive component. Nicotine binds to nicotinic acetylcholine receptors (nAChR) to produce its initial effects. The nAChRs subtypes are composed of five subunits that can form in numerous combinations with varied functional and pharmacological characteristics. Diverse psychopharmacological effects contribute to the overall process of nicotine addiction, but two general neural systems are emerging as critical for the initiation and maintenance of tobacco use. Mesocorticolimbic circuitry that includes the dopaminergic pathway originating in the ventral tegmental area and projecting to the nucleus accumbens is recognized as vital for reinforcing behaviors during the initiation of nicotine addiction. In this neural system β2, α4, and α6 are the most important nAChR subunits underlying the rewarding aspects of nicotine and nicotine self-administration. On the other hand, the epithalamic habenular complex and the interpeduncular nucleus, which are connected via the fasciculus retroflexus, are critical contributors regulating nicotine dosing and withdrawal symptoms. In this case, the α5 and β4 nAChR subunits have critical roles in combination with other subunits. In both of these neural systems, particular nAChR subtypes have roles that contribute to the overall nicotine addiction process
Biophysical Journal, Sep 1, 1993
The amino acid located at position 369 is a key determinant of the ion conduction pathway or pore... more The amino acid located at position 369 is a key determinant of the ion conduction pathway or pore of the voltage-gated K+ channels, Kv2.1 and a chimeric channel, CHM, constructed by replacing the pore region of Kv2.1 with that of Kv3.1. To determine the orientation of residue 369 with respect to the aqueous lumen of the pore, the nonpolar lie at 369 in Kv2.1 was replaced with a basic His. This substitution produced a Cs'-selective channel with Cs+:K+ permeability ratio of 4 compared to 0.1 in the wild type. Block by external tetraethylammonium (TEA) was reduced about 20-fold, while block by internal TEA was unaffected. External protons and Zn2+, that are known to interact with the imidazole ring of His, blocked the mutant channel much more effectively than the wild type channel. The blockade by Zn2+ and protons was voltage-independent, and the proton blockade had a pKa of about 6.5, consistent with the pKI for His in solution. The histidyl-specific reagent diethylpyrocarbonate produced greatly exaggerated blockade of the mutated channel compared to the wild type. The residue at position 369 appears to form part of the binding site for external TEA and to influence the selectivity for monovalent cations. We suggest that the imidazole side-chain of His369 is exposed to the aqueous lumen at a surface position near the external mouth of the pore.
eLife, Jan 31, 2020
The extensive feedback from the auditory cortex (AC) to the inferior colliculus (IC) supports cri... more The extensive feedback from the auditory cortex (AC) to the inferior colliculus (IC) supports critical aspects of auditory behavior but has not been extensively characterized. Previous studies demonstrated that activity in IC is altered by focal electrical stimulation and pharmacological inactivation of AC, but these methods lack the ability to selectively manipulate projection neurons. We measured the effects of selective optogenetic modulation of corticocollicular feedback projections on IC sound responses in mice. Activation of feedback increased spontaneous activity and decreased stimulus selectivity in IC, whereas suppression had no effect. To further understand how microcircuits in AC may control collicular activity, we optogenetically modulated the activity of different cortical neuronal subtypes, specifically parvalbumin-positive (PV) and somatostatin-positive (SST) inhibitory interneurons. We found that modulating the activity of either type of interneuron did not affect IC sound-evoked activity. Combined, our results identify that activation of excitatory projections, but not inhibition-driven changes in cortical activity, affects collicular sound responses.
FEBS Letters, Mar 13, 1995
We report the cloning and functional expression of a novel K + channel ~-subunit from human atriu... more We report the cloning and functional expression of a novel K + channel ~-subunit from human atrium, hKv~13, hKv/33 is highly homologous to the two D-subunits cloned from rat brain, Kv/]l and Kv~2, but has an essentially unique stretch of 79 N-terminal residues. Upon expression in Xenopus oocytes, hKvi~3 accelerates the inactivation of co-injected hKvl.4 currents and induces fast inactivation of non-inactivating co-injected hKvl.5 currents. By contrast, hKvi~13 had no effect on hKvl.1, hKvl.2, or hKv2.1 currents. Thus, hKv/]3 represents a third type of K ÷ channel ~-subunit which modulates the kinetics of a unique subset of channels in the Kv| subfamily.
Atherosclerosis, Dec 1, 1989
Nature Precedings, Mar 28, 2011
Genome wide association studies (GWAS) have identified more than 200, mostly novel common lowpene... more Genome wide association studies (GWAS) have identified more than 200, mostly novel common lowpenetrance susceptibility loci for a range of different cancer types. The predicted risk associated with each locus is generally modest (per allele odds ratios usually ranging from 1.15 to 1.3) and so, presumably, are the functional effects of individual genetic variants conferring disease susceptibility. Perhaps the greatest challenge in the 'post-GWAS' era is to understand the functional consequences underlying these loci. In doing so, novel biological insights may be revealed leading to clinical benefits, including the development of reliable biomarkers, effective screening and disease prevention strategies. The purpose of this article is to propose some principles for the initial functional characterization of cancer risk loci, with a focus on non-coding variants, and to define 'post-GWAS' functional characterisation.
Pharmacological Research, Nov 1, 1989
Artery, 1989
Three sets of parameters, (i) relaxation to acetylcholine (Ach), ATP and NaNO2, (ii) cholesterol ... more Three sets of parameters, (i) relaxation to acetylcholine (Ach), ATP and NaNO2, (ii) cholesterol content in aortic tissue, and (iii) energy metabolism were compared in normal and atherosclerotic rabbits, fed 1% cholesterol for eight weeks. A special protocol was envisaged to permit a strict comparison between Ach, ATP and NaN O2 at different levels of thoracic aorta, in each rabbit. A gradual impairment of the endothelium-dependent relaxation to Ach and ATP was found at different levels of the thoracic aorta from hypercholesteromic rabbits. By contrast, NaNO2--endothelium-independent--maintained its relaxing power quite normally at all aortic levels. A close correlation was evident between the impairment of aorta relaxation to Ach and the cholesterol infiltration in the vessel wall, being the correlation coefficient -0.85 (P less than 0.001). A correlation was also evident for ATP, but to a lower degree, being the correlation coefficient -0.61 (P less than 0.01). Energy metabolism a...
CARS imaging of ex vivo ovarian cancer samples
CARS imaging of ex vivo ovarian cancer samples
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling... more Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/ Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. Ó2018 AACR.
eLife, Mar 15, 2022
Sensory systems must account for both contextual factors and prior experience to adaptively engag... more Sensory systems must account for both contextual factors and prior experience to adaptively engage with the dynamic external environment. In the central auditory system, neurons modulate their responses to sounds based on statistical context. These response modulations can be understood through a hierarchical predictive coding lens: responses to repeated stimuli are progressively decreased, in a process known as repetition suppression, whereas unexpected stimuli produce a prediction error signal. Prediction error incrementally increases along the auditory hierarchy from the inferior colliculus (IC) to the auditory cortex (AC), suggesting that these regions may engage in hierarchical predictive coding. A potential substrate for top-down predictive cues is the massive set of descending projections from the AC to subcortical structures, although the role of this system in predictive processing has never been directly assessed. We tested the effect of optogenetic inactivation of the auditory cortico-collicular feedback in awake mice on responses of IC neurons to stimuli designed to test prediction error and repetition suppression. Inactivation of the cortico-collicular pathway led to a decrease in prediction error in IC. Repetition suppression was unaffected by cortico-collicular inactivation, suggesting that this metric may reflect fatigue of bottom-up sensory inputs rather than predictive processing. We also discovered populations of IC units that exhibit repetition enhancement, a sequential increase in firing with stimulus repetition. Cortico-collicular inactivation led to a decrease in repetition enhancement in the central nucleus of IC, suggesting that it is a top-down phenomenon. Negative prediction error, a stronger response to a tone in a predictable rather than unpredictable sequence, was suppressed in shell IC units during cortico-collicular inactivation. These changes in predictive coding metrics arose from bidirectional modulations in the response to the standard and deviant contexts, such that the units in IC responded more similarly to each context in the absence of cortical input. We also investigated how these metrics compare between the anesthetized and awake states by recording from the same units under both conditions. We found that metrics of predictive coding and deviance detection differ depending on the anesthetic state of the animal, with negative prediction error emerging in the central IC and repetition enhancement and prediction error being more prevalent in the absence of anesthesia. Overall, our results demonstrate that the AC provides cues about the statistical context of sound to subcortical brain regions via direct feedback, regulating processing of both prediction and repetition.
The FASEB Journal, Aug 25, 2010
α6* (asterisk indicates the presence of additional subunits) nicotinic acetylcholine receptors (n... more α6* (asterisk indicates the presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) are broadly implicated in catecholamine‐dependent disorders that involve attention, motor movement, and nicotine self‐administration. Different molecular forms of 06 nAChRs mediate catechol‐amine release, but receptor differentiation is greatly hampered by a paucity of subtype selective ligands. 0‐Conotoxins are nAChR‐targeted peptides used by Conus species to incapacitate prey. We hypothesized that distinct conotoxin‐binding kinetics could be exploited to develop a series of selective probes to enable study of native receptor subtypes. Proline6 of 0‐conotoxin BuIA was found to be critical for nAChR selectivity; substitution of proline6 with 4‐hydroyx‐proline increased the IC50 by 2800‐fold at 06/o3β2β3 but only by 6‐fold at o6/o3β4 nAChRs (to 1300 and 12 nM, respectively). We used conotoxin probes together with subunit‐null mice to interrogate nAChR subtypes that modulate hippocampal norepi‐nephrine release. Release was abolished in 06‐null mutant mice. 0‐Conotoxin BuIA[T5A;P6O] partially blocked norepinephrine release in wild‐type controls but failed to block release in β4_/_ mice. In contrast, BuIA[T5A;P6O] failed to block dopamine release in the wild‐type striatum known to contain o6β2* nAChRs. BuIA[T5A;P6O] is a novel ligand for distinguishing between closely related 06* nAChRs; o6β4* nAChRs modulate norepinephrine release in hippocampus but not dopamine release in stria‐tum.—Azam, L., Maskos, U., Changeux, J.‐P., Dow‐ell, C. D., Christensen, S., De Biasi, M., McIntosh, J. M. o‐Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between o6β4 and o6β2 nAChRs and blocks nicotine‐stimulated norepinephrine release. FASEBJ. 24, 5113–5123 (2010). www.fasebj.org
Neuropharmacology, Sep 1, 2022
bioRxiv (Cold Spring Harbor Laboratory), Oct 21, 2022
Nicotine is an addictive drug whose popularity has recently increased, particularly among adolesc... more Nicotine is an addictive drug whose popularity has recently increased, particularly among adolescents, due to the availability of electronic nicotine devices (i.e., "vaping") and nicotine eliquids containing additives with rich chemosensory properties. Some efforts to understand the role of these additives in nicotine reward suggest that they increase nicotine reward and reinforcement, but the sensory contributions of additives, especially in their vapor forms, are largely untested. Here, to better understand how a fruit-flavored (i.e., strawberry) additive influences nicotine reward and aversion, we used a conditioned place preference (CPP) procedure in which nicotine and a strawberry additive were delivered as a vapor to male and female adolescent mice. We found that nicotine vapor alone can lead to dose-dependent CPP when using a biased design. The strawberry additive did not produce CPP on its own, and we did not observe an effect of the strawberry additive on nicotine vapor-induced reward. Nevertheless, mice exposed to nicotine + strawberry additive vapor had higher plasma cotinine concentrations,. CC-BY-NC-ND 4.
bioRxiv (Cold Spring Harbor Laboratory), Apr 26, 2021
Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide... more Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide. Topiramate (TPM) is an antiepileptic drug that has been shown to reduce ethanol drinking in humans. However, TPM is associated with a variety of adverse effects due to its interaction with many receptor systems and intracellular pathways. Thus, a better understanding of the role of TPM's main molecular targets in AUD could yield better therapeutic tools. GluK1-containing kainate receptors (GluK1*KARs) are non-selectively inhibited by TPM, and genetic association studies suggest that this receptor system could be targeted to reduce drinking in AUD patients. We examined the efficacy of LY466195, a selective inhibitor of GluK1*KAR, in reducing ethanol consumption in the intermittent two-bottle choice paradigm in mice. The effect of LY466195 on various ethanol-related phenotypes was investigated by quantification of alcohol intake, physical signs of withdrawal, conditioned place preference (CPP) and in vivo microdialysis in the nucleus accumbens. Selective GluK1*KAR inhibition reduced ethanol intake and preference in a dosedependent manner. LY466195 treatment attenuated the physical manifestations of ethanol withdrawal and influenced the rewarding properties of ethanol. Interestingly, LY466195 injection also normalized changes in dopamine levels in response to acute ethanol in ethanol-dependent mice, but had no effect in ethanol-naïve mice, suggesting ethanol state-dependent effects. The data point to GluK1*KARs as an attractive pharmacological target for the treatment of AUD.
Neuropharmacology, Oct 1, 2020
The popularity of e-cigarettes has skyrocketed in recent years, and most vapers use flavored e-ci... more The popularity of e-cigarettes has skyrocketed in recent years, and most vapers use flavored e-cigarette products. Consumption of flavored e-cigarettes exceeds that of combustible cigarettes and other tobacco products among adolescents, who are particularly vulnerable to becoming nicotine dependent. Flavorings have been used by the tobacco industry since the 17th century, but the use of flavors by the e-cigarette industry to create products with “characterizing” flavors (i.e. flavors other than tobacco or menthol) has sparked a public health debate. This review addresses the possibility that characterizing flavors make nicotine more appealing, rewarding and addictive. It also discusses ways in which preclinical and clinical studies could improve our understanding of the mechanisms by which flavors may alter nicotine reward and reinforcement.This article is part of the special issue on ‘Contemporary Advances in Nicotine Neuropharmacology’.
Journal of Addiction Research and Therapy, 2012
Tobacco use is a major health problem, and nicotine is the main addictive component. Nicotine bin... more Tobacco use is a major health problem, and nicotine is the main addictive component. Nicotine binds to nicotinic acetylcholine receptors (nAChR) to produce its initial effects. The nAChRs subtypes are composed of five subunits that can form in numerous combinations with varied functional and pharmacological characteristics. Diverse psychopharmacological effects contribute to the overall process of nicotine addiction, but two general neural systems are emerging as critical for the initiation and maintenance of tobacco use. Mesocorticolimbic circuitry that includes the dopaminergic pathway originating in the ventral tegmental area and projecting to the nucleus accumbens is recognized as vital for reinforcing behaviors during the initiation of nicotine addiction. In this neural system β2, α4, and α6 are the most important nAChR subunits underlying the rewarding aspects of nicotine and nicotine self-administration. On the other hand, the epithalamic habenular complex and the interpeduncular nucleus, which are connected via the fasciculus retroflexus, are critical contributors regulating nicotine dosing and withdrawal symptoms. In this case, the α5 and β4 nAChR subunits have critical roles in combination with other subunits. In both of these neural systems, particular nAChR subtypes have roles that contribute to the overall nicotine addiction process
Biophysical Journal, Sep 1, 1993
The amino acid located at position 369 is a key determinant of the ion conduction pathway or pore... more The amino acid located at position 369 is a key determinant of the ion conduction pathway or pore of the voltage-gated K+ channels, Kv2.1 and a chimeric channel, CHM, constructed by replacing the pore region of Kv2.1 with that of Kv3.1. To determine the orientation of residue 369 with respect to the aqueous lumen of the pore, the nonpolar lie at 369 in Kv2.1 was replaced with a basic His. This substitution produced a Cs'-selective channel with Cs+:K+ permeability ratio of 4 compared to 0.1 in the wild type. Block by external tetraethylammonium (TEA) was reduced about 20-fold, while block by internal TEA was unaffected. External protons and Zn2+, that are known to interact with the imidazole ring of His, blocked the mutant channel much more effectively than the wild type channel. The blockade by Zn2+ and protons was voltage-independent, and the proton blockade had a pKa of about 6.5, consistent with the pKI for His in solution. The histidyl-specific reagent diethylpyrocarbonate produced greatly exaggerated blockade of the mutated channel compared to the wild type. The residue at position 369 appears to form part of the binding site for external TEA and to influence the selectivity for monovalent cations. We suggest that the imidazole side-chain of His369 is exposed to the aqueous lumen at a surface position near the external mouth of the pore.
eLife, Jan 31, 2020
The extensive feedback from the auditory cortex (AC) to the inferior colliculus (IC) supports cri... more The extensive feedback from the auditory cortex (AC) to the inferior colliculus (IC) supports critical aspects of auditory behavior but has not been extensively characterized. Previous studies demonstrated that activity in IC is altered by focal electrical stimulation and pharmacological inactivation of AC, but these methods lack the ability to selectively manipulate projection neurons. We measured the effects of selective optogenetic modulation of corticocollicular feedback projections on IC sound responses in mice. Activation of feedback increased spontaneous activity and decreased stimulus selectivity in IC, whereas suppression had no effect. To further understand how microcircuits in AC may control collicular activity, we optogenetically modulated the activity of different cortical neuronal subtypes, specifically parvalbumin-positive (PV) and somatostatin-positive (SST) inhibitory interneurons. We found that modulating the activity of either type of interneuron did not affect IC sound-evoked activity. Combined, our results identify that activation of excitatory projections, but not inhibition-driven changes in cortical activity, affects collicular sound responses.
FEBS Letters, Mar 13, 1995
We report the cloning and functional expression of a novel K + channel ~-subunit from human atriu... more We report the cloning and functional expression of a novel K + channel ~-subunit from human atrium, hKv~13, hKv/33 is highly homologous to the two D-subunits cloned from rat brain, Kv/]l and Kv~2, but has an essentially unique stretch of 79 N-terminal residues. Upon expression in Xenopus oocytes, hKvi~3 accelerates the inactivation of co-injected hKvl.4 currents and induces fast inactivation of non-inactivating co-injected hKvl.5 currents. By contrast, hKvi~13 had no effect on hKvl.1, hKvl.2, or hKv2.1 currents. Thus, hKv/]3 represents a third type of K ÷ channel ~-subunit which modulates the kinetics of a unique subset of channels in the Kv| subfamily.
Atherosclerosis, Dec 1, 1989
Nature Precedings, Mar 28, 2011
Genome wide association studies (GWAS) have identified more than 200, mostly novel common lowpene... more Genome wide association studies (GWAS) have identified more than 200, mostly novel common lowpenetrance susceptibility loci for a range of different cancer types. The predicted risk associated with each locus is generally modest (per allele odds ratios usually ranging from 1.15 to 1.3) and so, presumably, are the functional effects of individual genetic variants conferring disease susceptibility. Perhaps the greatest challenge in the 'post-GWAS' era is to understand the functional consequences underlying these loci. In doing so, novel biological insights may be revealed leading to clinical benefits, including the development of reliable biomarkers, effective screening and disease prevention strategies. The purpose of this article is to propose some principles for the initial functional characterization of cancer risk loci, with a focus on non-coding variants, and to define 'post-GWAS' functional characterisation.
Pharmacological Research, Nov 1, 1989
Artery, 1989
Three sets of parameters, (i) relaxation to acetylcholine (Ach), ATP and NaNO2, (ii) cholesterol ... more Three sets of parameters, (i) relaxation to acetylcholine (Ach), ATP and NaNO2, (ii) cholesterol content in aortic tissue, and (iii) energy metabolism were compared in normal and atherosclerotic rabbits, fed 1% cholesterol for eight weeks. A special protocol was envisaged to permit a strict comparison between Ach, ATP and NaN O2 at different levels of thoracic aorta, in each rabbit. A gradual impairment of the endothelium-dependent relaxation to Ach and ATP was found at different levels of the thoracic aorta from hypercholesteromic rabbits. By contrast, NaNO2--endothelium-independent--maintained its relaxing power quite normally at all aortic levels. A close correlation was evident between the impairment of aorta relaxation to Ach and the cholesterol infiltration in the vessel wall, being the correlation coefficient -0.85 (P less than 0.001). A correlation was also evident for ATP, but to a lower degree, being the correlation coefficient -0.61 (P less than 0.01). Energy metabolism a...