Huda Akil - Academia.edu (original) (raw)
Papers by Huda Akil
Proceedings of the National Academy of Sciences of the United States of America, 1994
A full-length cDNA encoding the guinea pig kappa opioid (dynorphin) receptor has been isolated. T... more A full-length cDNA encoding the guinea pig kappa opioid (dynorphin) receptor has been isolated. The deduced protein contains 380 aa and seven hydrophobic alpha-helices characteristic of the G protein-coupled receptors. This receptor is 90% identical to the mouse and rat kappa receptors, with the greatest level of divergence in the N-terminal region. When expressed in COS-7 cells, the receptor displays high affinity and stereospecificity toward dynorphin peptides and other kappa-selective opioid ligands such as U50, 488. It does not bind the mu- and delta-selective opioid ligands. The expressed receptor is functionally coupled to G protein(s) to inhibit adenylyl cyclase and Ca2+ channels. The guinea pig kappa receptor mRNA is expressed in many brain areas, including the cerebellum, a pattern that agrees well with autoradiographic maps of classical guinea pig kappa binding sites. Species differences in the pharmacology and mRNA distribution between the cloned guinea pig and rat kappa ...
Proceedings of the National Academy of Sciences, 2020
The pioneering neuroscientist Bruce McEwen died on January 2, 2020 at the age of 81 following a b... more The pioneering neuroscientist Bruce McEwen died on January 2, 2020 at the age of 81 following a brief illness. He was the Alfred E. Mirsky Professor and head of the Harold and
Computational Systems Bioinformatics. CSB2003. Proceedings of the 2003 IEEE Bioinformatics Conference. CSB2003
Extracting and identifying gene and protein names from literature is a critical step for mining f... more Extracting and identifying gene and protein names from literature is a critical step for mining functional information of genes and proteins. While extensive efforts have been devoted to this important task, most of them were aiming at extracting gene/protein name per se without paying much attention to associate the extracted name with existing gene and protein database entries. We developed a simple and efficient method to identify gene and protein names in literature using a combination of heuristic and statistical strategies. Our approach will map the extracted names to individual LocusLink entries thus enable the seamless integration of literature information with existing gene/protein databases. Evaluation on a test corpus shows that our method can achieve both high recall and precision. Our method exhibits good performance and can be used as a building block for large biomedical literature mining systems.
Regulatory Peptides, 1994
Molecular Brain Research, 1997
The present study was undertaken to analyze the expression of two opioid receptor genes m and k i... more The present study was undertaken to analyze the expression of two opioid receptor genes m and k in different gastrointestinal regions of the rat. A combination of mRNA quantification and immunohistochemical visualization was used to characterize their expression. Using naive animals, RNA was extracted from tissues and used in RNase protection assays: both receptor mRNAs were expressed in all investigated areas but displayed different expression profiles across the various regions of the digestive tract. Stomach and proximal colon appeared to have the highest expression levels of both receptors, whereas the lowest expression levels were found in the duodenum. Expression levels for both receptors were always lower in the gastrointestinal tract compared to the brain. However, the k-receptor expression in the proximal colon represented 40% of the amount found in the brain, which is almost 4 times as high as the respective m-receptor expression. In contrast to smooth muscle cells, myenteric plexus perikarya of the rat stomach and colon were immunoreactive with antibodies raised against the C-termini of both kand m-opioid receptors. Numerous nerve fibers were also immunoreactive for both mand k-receptors and distributed in the longitudinal and circular muscle layers. Small perikarya immunoreactive for m-receptor were localized around the myenteric plexus and at the submucosal border of the circular muscle, whereas only few perikarya were immunoreactive for the k-receptor. We conclude that at least in rat stomach and colon, mand k-opioid receptors may directly control neuronal communication but seem to have no direct influence on smooth muscle cells.
Archives of General Psychiatry, 2003
Background: Negative feedback regulation of the hypothalamic-pituitary-adrenal axis occurs throug... more Background: Negative feedback regulation of the hypothalamic-pituitary-adrenal axis occurs through a dualreceptor system of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Their affinity for cortisol and their distribution in the brain differ. Studies using an MR antagonist have demonstrated that MR is active throughout the circadian rhythm. Because major depression is accompanied by increased glucocorticoid secretion and insensitivity to glucocorticoid feedback, and because glucocorticoids are capable of down-regulating MR and GR, we expected that major depression would be accompanied by decreased MR activity. Methods: To test this hypothesis, we administered spironolactone, an MR antagonist, to individuals with major depression and matched control subjects and assessed levels of corticotropin and cortisol secretion in response to this acute challenge. Studies were conducted in the morning, the time of peak activation of the hypothalamicpituitary-adrenal axis. All patients were currently depressed and free of all medications. All controls were free of all psychiatric diagnoses and of all medications. Results: Spironolactone treatment resulted in a significant increase in cortisol secretion levels in both groups. Depressed patients demonstrated higher cortisol secretion levels than control subjects. In addition, depressed patients demonstrated a different pattern of increase in cortisol secretion levels after spironolactone administration. Furthermore, a significant effect of spironolactone treatment on corticotropin secretion levels can be observed in depressed patients, whereas controls show no such effect. Conclusions: Despite high baseline cortisol levels, patients with major depression show high functional activity of the MR system. Paired with the body of evidence regarding decreased sensitivity to GR agonists, these data suggest an imbalance in the MR/GR ratio. The balance of MR and GR is known to affect brain serotonin systems and may play an etiologic role in serotonin receptor changes observed in patients with major depression.
Neuropsychopharmacology, 2009
after a year-long battle with leukemia. She was 59 years old. Dr Young was an internationally ren... more after a year-long battle with leukemia. She was 59 years old. Dr Young was an internationally renowned biological psychiatrist who conducted seminal work on stress biology and its role in severe depression and other mood disorders. She was elected to the ACNP in 1996. Elizabeth was raised in the Detroit and Chicago area, earned her medical degree from the Ohio State University in 1976, and completed her residency in Psychiatry at the same institution in 1979. Elizabeth came to the University of Michigan Medical School in July 1979 as a research fellow in the Department of Psychiatry. In 1981 she received a postdoctoral fellowship to work in the laboratories of Drs Huda Akil and Stanley Watson at the MBNI. She went on to join the faculty of the MBNI and Psychiatry, where she moved through the ranks to the senior positions that she occupied at the time of her death. Dr Young was the quintessential translational physician scientistFa role that she fashioned for herself before its critical importance was widely appreciated. Early in her
Annual Review of Neuroscience
Opioid addiction and overdose are at record levels in the United States. This is driven, in part,... more Opioid addiction and overdose are at record levels in the United States. This is driven, in part, by their widespread prescription for the treatment of pain, which also increased opportunity for diversion by sensation-seeking users. Despite considerable research on the neurobiology of addiction, treatment options for opioid abuse remain limited. Mood disorders, particularly depression, are often comorbid with both pain disorders and opioid abuse. The endogenous opioid system, a complex neuromodulatory system, sits at the neurobiological convergence point of these three comorbid disease states. We review evidence for dysregulation of the endogenous opioid system as a mechanism for the development of opioid addiction and/or mood disorder. Specifically, individual differences in opioid system function may underlie differences in vulnerability to opioid addiction and mood disorders. We also review novel research, which promises to provide more detailed understanding of individual differ...
Proceedings of the National Academy of Sciences
Artificially selected model organisms can reveal hidden features of the genetic architecture of t... more Artificially selected model organisms can reveal hidden features of the genetic architecture of the complex disorders that they model. Addictions are disease phenotypes caused by different intermediate phenotypes and pathways and thereby are potentially highly polygenic. High responder (bHR) and low responder (bLR) rat lines have been selectively bred (b) for exploratory locomotion (EL), a behavioral phenotype correlated with novelty-seeking, impulsive response to reward, and vulnerability to addiction, and is inversely correlated with spontaneous anxiety and depression-like behaviors. The rapid response to selection indicates loci of large effect for EL. Using exome sequencing of HR and LR rats, we identified alleles in gene-coding regions that segregate between the two lines. Quantitative trait locus (QTL) analysis in F2 rats derived from a bHR × bLR intercross confirmed that these regions harbored genes affecting EL. The combined effects of the seven genome-wide significant QTLs ...
The Journal of Neuroscience
The Journal of Neuroscience
Considerable evidence supports a role for brainstem adrenergic and noradrenergic inputs to cortic... more Considerable evidence supports a role for brainstem adrenergic and noradrenergic inputs to corticotropin-releasing hormone (CRH) cells of the hypothalamic paraventricular nucleus (PVN), in the control of hypothalamic-pituitary-adrenocortical (HPA) axis function. However, little is known about specific adrenoceptor (ADR) subtypes in CRH-containing cells of the PVN. Here we demonstrate, using dual in situ hybridization, that mRNA encoding ␣ 1b ADR is colocalized with CRH in the rat PVN. Furthermore, we confirm that these ␣ 1b ADR mRNAcontaining cells are stress-responsive, by colocalization with c-fos mRNA after restraint, swim, or immune stress. To determine whether expression of ␣ 1b ADR mRNA is influenced by circulating glucocorticoids, male rats underwent bilateral adrenalectomy (ADX) or sham surgery, and were killed after 1, 3, 7, or 14 d. In situ hybridization revealed levels of ␣ 1b ADR mRNA were increased in the PVN 7 and 14 d after ADX, but were not altered in the hippocampus, amygdala, or dorsal raphe. Additional rats underwent ADX or sham surgery and received a corticosterone pellet (10 or 50 mg) or placebo for 7 d. Corticosterone replacement (10 mg) reduced the ADX-induced increase in PVN ␣ 1b ADR mRNA to control levels, whereas 50 mg of corticosterone replacement resulted in a decrease in PVN ␣ 1b ADR mRNA as compared with all other groups. Furthermore, levels of plasma corticosterone were significantly correlated (inverse relationship) with ␣ 1b ADR mRNA in the PVN. We conclude that ␣ 1b ADR mRNA is expressed in CRHcontaining, stress-responsive cells of the PVN and is highly sensitive to circulating levels of corticosterone. Because activation of the ␣ 1B adrenoceptor is predominantly excitatory within the brain, we predict that this receptor plays an important role in facilitation of the HPA axis response.
Proceedings of the National Academy of Sciences of the United States of America, Oct 2, 2018
Two classes of peptide-producing neurons in the arcuate nucleus (Arc) of the hypothalamus are kno... more Two classes of peptide-producing neurons in the arcuate nucleus (Arc) of the hypothalamus are known to exert opposing actions on feeding: the anorexigenic neurons that express proopiomelanocortin (POMC) and the orexigenic neurons that express agouti-related protein (AgRP) and neuropeptide Y (NPY). These neurons are thought to arise from a common embryonic progenitor, but our anatomical and functional understanding of the interplay of these two peptidergic systems that contribute to the control of feeding remains incomplete. The present study uses a combination of optogenetic stimulation with viral and transgenic approaches, coupled with neural activity mapping and brain transparency visualization to demonstrate the following: () selective activation of Arc POMC neurons inhibits food consumption rapidly in unsated animals; () activation of Arc neurons arising from POMC-expressing progenitors, including POMC and a subset of AgRP neurons, triggers robust feeding behavior, even in the f...
PloS one, 2018
Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types... more Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this m...
Proceedings of the National Academy of Sciences of the United States of America, 1994
A full-length cDNA encoding the guinea pig kappa opioid (dynorphin) receptor has been isolated. T... more A full-length cDNA encoding the guinea pig kappa opioid (dynorphin) receptor has been isolated. The deduced protein contains 380 aa and seven hydrophobic alpha-helices characteristic of the G protein-coupled receptors. This receptor is 90% identical to the mouse and rat kappa receptors, with the greatest level of divergence in the N-terminal region. When expressed in COS-7 cells, the receptor displays high affinity and stereospecificity toward dynorphin peptides and other kappa-selective opioid ligands such as U50, 488. It does not bind the mu- and delta-selective opioid ligands. The expressed receptor is functionally coupled to G protein(s) to inhibit adenylyl cyclase and Ca2+ channels. The guinea pig kappa receptor mRNA is expressed in many brain areas, including the cerebellum, a pattern that agrees well with autoradiographic maps of classical guinea pig kappa binding sites. Species differences in the pharmacology and mRNA distribution between the cloned guinea pig and rat kappa ...
Proceedings of the National Academy of Sciences, 2020
The pioneering neuroscientist Bruce McEwen died on January 2, 2020 at the age of 81 following a b... more The pioneering neuroscientist Bruce McEwen died on January 2, 2020 at the age of 81 following a brief illness. He was the Alfred E. Mirsky Professor and head of the Harold and
Computational Systems Bioinformatics. CSB2003. Proceedings of the 2003 IEEE Bioinformatics Conference. CSB2003
Extracting and identifying gene and protein names from literature is a critical step for mining f... more Extracting and identifying gene and protein names from literature is a critical step for mining functional information of genes and proteins. While extensive efforts have been devoted to this important task, most of them were aiming at extracting gene/protein name per se without paying much attention to associate the extracted name with existing gene and protein database entries. We developed a simple and efficient method to identify gene and protein names in literature using a combination of heuristic and statistical strategies. Our approach will map the extracted names to individual LocusLink entries thus enable the seamless integration of literature information with existing gene/protein databases. Evaluation on a test corpus shows that our method can achieve both high recall and precision. Our method exhibits good performance and can be used as a building block for large biomedical literature mining systems.
Regulatory Peptides, 1994
Molecular Brain Research, 1997
The present study was undertaken to analyze the expression of two opioid receptor genes m and k i... more The present study was undertaken to analyze the expression of two opioid receptor genes m and k in different gastrointestinal regions of the rat. A combination of mRNA quantification and immunohistochemical visualization was used to characterize their expression. Using naive animals, RNA was extracted from tissues and used in RNase protection assays: both receptor mRNAs were expressed in all investigated areas but displayed different expression profiles across the various regions of the digestive tract. Stomach and proximal colon appeared to have the highest expression levels of both receptors, whereas the lowest expression levels were found in the duodenum. Expression levels for both receptors were always lower in the gastrointestinal tract compared to the brain. However, the k-receptor expression in the proximal colon represented 40% of the amount found in the brain, which is almost 4 times as high as the respective m-receptor expression. In contrast to smooth muscle cells, myenteric plexus perikarya of the rat stomach and colon were immunoreactive with antibodies raised against the C-termini of both kand m-opioid receptors. Numerous nerve fibers were also immunoreactive for both mand k-receptors and distributed in the longitudinal and circular muscle layers. Small perikarya immunoreactive for m-receptor were localized around the myenteric plexus and at the submucosal border of the circular muscle, whereas only few perikarya were immunoreactive for the k-receptor. We conclude that at least in rat stomach and colon, mand k-opioid receptors may directly control neuronal communication but seem to have no direct influence on smooth muscle cells.
Archives of General Psychiatry, 2003
Background: Negative feedback regulation of the hypothalamic-pituitary-adrenal axis occurs throug... more Background: Negative feedback regulation of the hypothalamic-pituitary-adrenal axis occurs through a dualreceptor system of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Their affinity for cortisol and their distribution in the brain differ. Studies using an MR antagonist have demonstrated that MR is active throughout the circadian rhythm. Because major depression is accompanied by increased glucocorticoid secretion and insensitivity to glucocorticoid feedback, and because glucocorticoids are capable of down-regulating MR and GR, we expected that major depression would be accompanied by decreased MR activity. Methods: To test this hypothesis, we administered spironolactone, an MR antagonist, to individuals with major depression and matched control subjects and assessed levels of corticotropin and cortisol secretion in response to this acute challenge. Studies were conducted in the morning, the time of peak activation of the hypothalamicpituitary-adrenal axis. All patients were currently depressed and free of all medications. All controls were free of all psychiatric diagnoses and of all medications. Results: Spironolactone treatment resulted in a significant increase in cortisol secretion levels in both groups. Depressed patients demonstrated higher cortisol secretion levels than control subjects. In addition, depressed patients demonstrated a different pattern of increase in cortisol secretion levels after spironolactone administration. Furthermore, a significant effect of spironolactone treatment on corticotropin secretion levels can be observed in depressed patients, whereas controls show no such effect. Conclusions: Despite high baseline cortisol levels, patients with major depression show high functional activity of the MR system. Paired with the body of evidence regarding decreased sensitivity to GR agonists, these data suggest an imbalance in the MR/GR ratio. The balance of MR and GR is known to affect brain serotonin systems and may play an etiologic role in serotonin receptor changes observed in patients with major depression.
Neuropsychopharmacology, 2009
after a year-long battle with leukemia. She was 59 years old. Dr Young was an internationally ren... more after a year-long battle with leukemia. She was 59 years old. Dr Young was an internationally renowned biological psychiatrist who conducted seminal work on stress biology and its role in severe depression and other mood disorders. She was elected to the ACNP in 1996. Elizabeth was raised in the Detroit and Chicago area, earned her medical degree from the Ohio State University in 1976, and completed her residency in Psychiatry at the same institution in 1979. Elizabeth came to the University of Michigan Medical School in July 1979 as a research fellow in the Department of Psychiatry. In 1981 she received a postdoctoral fellowship to work in the laboratories of Drs Huda Akil and Stanley Watson at the MBNI. She went on to join the faculty of the MBNI and Psychiatry, where she moved through the ranks to the senior positions that she occupied at the time of her death. Dr Young was the quintessential translational physician scientistFa role that she fashioned for herself before its critical importance was widely appreciated. Early in her
Annual Review of Neuroscience
Opioid addiction and overdose are at record levels in the United States. This is driven, in part,... more Opioid addiction and overdose are at record levels in the United States. This is driven, in part, by their widespread prescription for the treatment of pain, which also increased opportunity for diversion by sensation-seeking users. Despite considerable research on the neurobiology of addiction, treatment options for opioid abuse remain limited. Mood disorders, particularly depression, are often comorbid with both pain disorders and opioid abuse. The endogenous opioid system, a complex neuromodulatory system, sits at the neurobiological convergence point of these three comorbid disease states. We review evidence for dysregulation of the endogenous opioid system as a mechanism for the development of opioid addiction and/or mood disorder. Specifically, individual differences in opioid system function may underlie differences in vulnerability to opioid addiction and mood disorders. We also review novel research, which promises to provide more detailed understanding of individual differ...
Proceedings of the National Academy of Sciences
Artificially selected model organisms can reveal hidden features of the genetic architecture of t... more Artificially selected model organisms can reveal hidden features of the genetic architecture of the complex disorders that they model. Addictions are disease phenotypes caused by different intermediate phenotypes and pathways and thereby are potentially highly polygenic. High responder (bHR) and low responder (bLR) rat lines have been selectively bred (b) for exploratory locomotion (EL), a behavioral phenotype correlated with novelty-seeking, impulsive response to reward, and vulnerability to addiction, and is inversely correlated with spontaneous anxiety and depression-like behaviors. The rapid response to selection indicates loci of large effect for EL. Using exome sequencing of HR and LR rats, we identified alleles in gene-coding regions that segregate between the two lines. Quantitative trait locus (QTL) analysis in F2 rats derived from a bHR × bLR intercross confirmed that these regions harbored genes affecting EL. The combined effects of the seven genome-wide significant QTLs ...
The Journal of Neuroscience
The Journal of Neuroscience
Considerable evidence supports a role for brainstem adrenergic and noradrenergic inputs to cortic... more Considerable evidence supports a role for brainstem adrenergic and noradrenergic inputs to corticotropin-releasing hormone (CRH) cells of the hypothalamic paraventricular nucleus (PVN), in the control of hypothalamic-pituitary-adrenocortical (HPA) axis function. However, little is known about specific adrenoceptor (ADR) subtypes in CRH-containing cells of the PVN. Here we demonstrate, using dual in situ hybridization, that mRNA encoding ␣ 1b ADR is colocalized with CRH in the rat PVN. Furthermore, we confirm that these ␣ 1b ADR mRNAcontaining cells are stress-responsive, by colocalization with c-fos mRNA after restraint, swim, or immune stress. To determine whether expression of ␣ 1b ADR mRNA is influenced by circulating glucocorticoids, male rats underwent bilateral adrenalectomy (ADX) or sham surgery, and were killed after 1, 3, 7, or 14 d. In situ hybridization revealed levels of ␣ 1b ADR mRNA were increased in the PVN 7 and 14 d after ADX, but were not altered in the hippocampus, amygdala, or dorsal raphe. Additional rats underwent ADX or sham surgery and received a corticosterone pellet (10 or 50 mg) or placebo for 7 d. Corticosterone replacement (10 mg) reduced the ADX-induced increase in PVN ␣ 1b ADR mRNA to control levels, whereas 50 mg of corticosterone replacement resulted in a decrease in PVN ␣ 1b ADR mRNA as compared with all other groups. Furthermore, levels of plasma corticosterone were significantly correlated (inverse relationship) with ␣ 1b ADR mRNA in the PVN. We conclude that ␣ 1b ADR mRNA is expressed in CRHcontaining, stress-responsive cells of the PVN and is highly sensitive to circulating levels of corticosterone. Because activation of the ␣ 1B adrenoceptor is predominantly excitatory within the brain, we predict that this receptor plays an important role in facilitation of the HPA axis response.
Proceedings of the National Academy of Sciences of the United States of America, Oct 2, 2018
Two classes of peptide-producing neurons in the arcuate nucleus (Arc) of the hypothalamus are kno... more Two classes of peptide-producing neurons in the arcuate nucleus (Arc) of the hypothalamus are known to exert opposing actions on feeding: the anorexigenic neurons that express proopiomelanocortin (POMC) and the orexigenic neurons that express agouti-related protein (AgRP) and neuropeptide Y (NPY). These neurons are thought to arise from a common embryonic progenitor, but our anatomical and functional understanding of the interplay of these two peptidergic systems that contribute to the control of feeding remains incomplete. The present study uses a combination of optogenetic stimulation with viral and transgenic approaches, coupled with neural activity mapping and brain transparency visualization to demonstrate the following: () selective activation of Arc POMC neurons inhibits food consumption rapidly in unsated animals; () activation of Arc neurons arising from POMC-expressing progenitors, including POMC and a subset of AgRP neurons, triggers robust feeding behavior, even in the f...
PloS one, 2018
Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types... more Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this m...