Important Findings Published in Biological Psychiatry
By Caleb M. Adler, MD.
July 1, 2012
Commentary by Shigeto Yamamoto, Shigeru Morinobu, Yosuke Fujita, and Shigeto Yamawaki
Stafford JM, Raybuck JD, Ryabinin AE, et al (2012). Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry 72: 25-33.
Dr. Stafford and colleagues address the hypothesis that increased histone acetylation enhances memory consolidation. They use a mouse model in which intrahippocampal and intra-medial prefrontal administrations of the histone deacetylase inhibitor, sodium butyrate (NaB) were applied after contextual fear conditioning and extinction. They found NaB administration in the hippocampus was more closely associated with memory extinction than memory consolidation. In the commentary, Dr. Yamamoto and colleagues review the background of this work and compare these findings with other recent studies, suggesting potential clinical directions for future research.
Commentary by Patrick O. McGowan
Labonte B, Yerko V, Gross J, et al (2012). Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biol Psychiatry 72: 41-48.
In this paper, Dr. Labonte and colleagues follow up previous observations of epigenetic influences in the glucocorticoid receptor (GR). They find evidence for region-specific changes in in the hippocampal GR of suicide completers with a history of abuse, compared with individual without an abuse history who completed suicide, and other controls. In contrast, no group differences were observed in anterior cingulate GR. The commentary discusses the role of epigenetics in regulating long-term response to early life events, while high-lighting potential complications inherent in studies of this kind.
Commentary by Kelimer Lebron-Milad, Bronwyn M. Graham, and Mohammed R. Milad
Glover EM, Jovanovic T, Mercer KB, et al (2012). Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder. Biol Psychiatry 72: 19-24.
Several lines of evidence have suggested the potential influence of estrogen levels in fear extinction, and potentially post-traumatic stress disorder (PTSD). In this paper, the authors observed that women with PTSD and low estrogen levels showed greater fear-potentiated startle responses during fear extinction training than did women without PTSD. This difference was not observed in women with PTSD and high estrogen levels. The commentary notes how these findings compare with previous work by these authors and others; and discusses the potential implications of these findings, both for studying PTSD and for clinical interventions in this patient population.
July 15, 2012
Commentary by P. Read Montegue
"The Scylla and Charybdis of neuroeconomic approaches to psychopathology"
In this commentary directed at the contents of this special issue of Biological Psychiatry, the author discusses the application of neuroeconomics to understanding psychiatric disorders. He lays out important criteria for the approach and reviews the ways in which papers in this issue address the use of neuroeconomics; connecting neurocircuitry with psychopathology, studying social interaction, and utilizing neuroeconomics to gain insights into defined disorders. The commentary further discussed potential challenges facing the field in further applying these techniques to the understanding and treatment of psychiatric disorders.
Commentary by Cameron S. Carter
"Neuroeconomics: Sharpened tools of value for clinical cognitive and affective neuroscience"
The commentary discusses the application of neuroeconomics to studying the cognitive and neural underpinnings of psychopathology. Dr. Carter reviews the paradigmatic components of neuroeconomics and concludes that the approach may be best considered to be a rapidly developing area within cognitive, affective, and social neuroscience. The commentary further described ways in which this approach has contributed to conceptualizing psychiatric disorders and suggests ways to optimize the application of neuroeconomics to psychiatry in the future.
Commentary by Monique Ernst
"The usefulness of neuroeconomics for the study of depression across adolescence into adulthood"
This commentary focuses on the utility of pairing prospect theory with prediction error theory to study neural changes that reflect valuation processes. Dr. Ernst notes that depression in particular, involves changes in patterns of valuation and choice that appear to implement networks involved in emotional expression and regulation, motivation and elements of executive function. Further, changes in these networks with maturation may be related to the onset and development of mood symptoms in adolescence and through adulthood. Future experimental approaches building on current findings are discussed in some detail.
August 1, 2012
Commentary by Eric J. Nestler and John H. Krystal
"Planning the new national institute on substance use and addiction disorders"
The commentary discusses the recent decision by the National Institutes of Health (NIH) to consolidate addiction research into a new institute, the National Institute on Substance Use and Addiction Disorders (NISUAD). This change would involve the incorporation of the National Institutes on Drug Abuse (NIDA) and Alcohol Abuse and Alcoholism (NIAAA) into the NISUAD, as well as the potential adoption of other addiction related research from institutes across the NIH. Drs. Nestler and Krystal discuss the potential benefits of these changes, as well as the potential risks to the already under-funded study of addictive disorders.
Commentary by Enrico Brunetti and Fabio Malavasi
Feldman R, Zagoory-Sharon O, Weisman O, et al (2012). Sensitive Parenting Is Associated with Plasma Oxytocin and Polymorphisms in the OXTR and CD38 Genes. Biol Psychiatry 72:175-181.
A broad range of studies have implicated oxytocin (OT) in maternal behaviors. More recently variations in the OT receptor (OXTR) have also been implicated in social interactions, as has the CD38 ectoenzyme that has been found to mediate the release of OT in the brain. Furthermore, OXTR and CD38 risk alleles for autism spectrum disorders have been associated with deficits in social behaviors. In this paper, Dr. Feldman and colleagues examined a group of parents with four to six month-old infants. They report their findings that OXTR and CD38 risk alleles were associated with lower plasma levels of OT; and that both the presence of risk alleles and lower levels of OT were associated with less parental touch. In contrast, the combination of low-risk alleles and higher OT was associated with increased gaze synchrony between parents and off-spring. In addition, they found that individuals who reported having received greater parental care in childhood had higher levels of plasma OT in the present, and were more likely to possess lower-risk CD38 alleles-as well as to demonstrate greater infant touch. In the commentary, Drs. Brunette and Malavasi summarize current thoughts around the role of OT pathways in psychiatric disorders, including the many remaining unknowns.
Commentary by Anissa Abi-Dargham
Love TM, Enoch MA, Hodgkinson CA, et al (2012). Oxytocin gene polymorphisms influence human dopaminergic function in a sex-dependent manner. Biol Psychiatry 72: 198-206.
In this study, Dr. Love and colleagues report on their finding an association between genetic variation within the oxytocin gene (OXT) and dopamine release in response to stress. They found that specific alleles in a group of healthy women correlated with increased dopamine release after a pain-stress stimulus, in a portion of the right ventromedial caudate. These findings were sex-specific; no such correlation was observed in the men tested. In addition, specific genetic variations and dopamine release were associated with at least some behavioral findings in the women tested. Only an association between stress-induced dopamine release and trait anxiety was seen in men. In the commentary, these findings are placed in the larger context of recent oxytocin research. Limitations of this study are discussed, as are potential follow-up studies.
Commentary by Detlef H. Heck and Lu Lu
Kaphzan H, Hernandez P, Jung JI, et al (2012). Reversal of Impaired Hippocampal Long-Term Potentiation and Contextual Fear Memory Deficits in Angelman Syndrome Model Mice by ErbB Inhibitors. Biol Psychiatry 72: 182-190.
Angelman syndrome (AS) is an autism spectrum disorder most commonly caused by chromosome 15 deletions encompassing the UBE3A gene. The authors have previously created a mouse model of AS which shares many features of the syndrome. The UBE3A gene has also been linked to schizophrenia, which includes some clinical elements in common with AS. In this study, Dr. Kaphzan and colleagues extended previous observations of alterations in the NRG1-ErbB4 pathway in patients with schizophrenia by measuring expression of neuregulin 1 and ErbB4 receptors in their AS model mice. They found evidence of increased neuregulin-ErbB4 signaling in the hippocampus of these mice; and further noted that ErbB4 inhibitors could both reverse changes in long-term potentiation, and enhance long-term contextual fear memory in the AS model mice. In the commentary, Drs. Heck and Lu note that these findings suggest a common deficit in synaptic communication across disparate psychiatric disorders. They expand on these findings by noting evidence for relationships between some of the genes involved. The commentary further elaborates on the support provided both for suggestions that synaptic changes may be a critical component of normal learning, and that related pathology might play a role in psychiatric illness.
August 15, 2012
Commentary by Mark A. Smith and Sanjeev Pathak
"The promise of rapidly acting antidepressants: Challenges and Opportunities"
The commentary addresses the recent increased interest in rapidly acting antidepressants, sparked by findings that ketamine infusion appears to be associated with rapid antidepressant response. Drs. Smith and Pathak discuss measurement parameters that need to be considered in evaluation prospective agents, as well as the lack of data with regard to longer-term treatment. Directions for future research are explored.
Commentary by Cortney A. Turner, Stanley J. Watson, and Huda Akil
Elsayed M, Banasr M, Duric V, et al (2012). Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression. Biol Psychiatry 72: 258-265.
Fibroblast growth factor-2 (FGF-2) has been found to both respond to anxiety and depression in rodent stress models, and to mediate the effects of antidepressant and anxiolytic interventions. In this paper, previous findings were extended by exposing groups of rodents to chronic, unpredictable stress (CUS) paradigms. The authors found chronic FGF-2 intracerebroventricular infusions blocked some effects of CUS exposure. Further, the mitigating influence of antidepressants on the effects of CUS was vitiated by an inhibitor of FGF-2 receptor signaling. The authors also found that FGF-2 demonstrated direct antidepressant and anxiolytic action when infused into the prefrontal cortex. In the commentary, these findings are placed in the larger context of recent FGF-2 findings, and future research directions are explored.
Commentary by Mounira Banasr and Ronald S. Duman
Koehl M, van der Veen R, Gonzales D, et al (2012). Interplay of maternal care and genetic influences in programming adult hippocampal neurogenesis. Biol Psychiatry 72: 282-289.
In this paper, the authors strove to disentangle the effects of maternal behavior from genetic influences on hippocampal neurogenesis. Inbred mice were fostered by unrelated mothers from mouse strains known to exhibit differing pup-oriented behavior. Dr. Koehl and colleagues found that maternal environment impacted features of newborn granule cells in the dentate gyrus of the hippocampus only in the more genetically vulnerable mouse strain. The commentary describes the study at length, and notes congruent and disparate findings from other recent studies by this group and others. Drs. Banasr and Duman further describe the further questions now raised by these findings.
September 1, 2012
Commentary by Marco Koch and Tamas L. Horvath
Davis JF, Schurdak JD, Magrisso IJ, et al (2012). Gastric bypass surgery attenuates ethanol consumption in ethanol-preferring rats. Biol Psychiatry 72: 354-360.
Recent studies have suggested that in addition to promoting weight loss, Roux-en-Y gastric bypass (RYGB) surgery may decrease some reward-related behaviors. In this paper, the investigators used a review of human patients coupled with a pre-clinical study in rats to investigate the impact of RYGB on ethanol consumption. Dr. Davis and colleagues observed that ethanol consumption declined over an average of ~190 weeks in post-operative patients who reported frequent pre-operative consumption. In rats, the RYGB was similarly associated with decreased ethanol intake, and these effects correlated with ethanol-induced increases in glucagon-like peptide-1 (GLP-1), an anorexigenic gut hormone. Further, administration of GLP-1 agonists decreased ethanol consumption in those rats who did not receive the RYGB procedure, while the orexigenic gut hormone ghrelin inhibited the effects of the RYGB on ethanol intake.
Perelló M, Zigman JM (2012). The role of ghrelin in reward-based eating. Biol Psychiatry 72: 347-353.
In this review article, Drs. Perelló and Zigman discuss recent research into the orexigenic hormone, ghrelin. In addition to its effects on body weight homeostasis, ghrelin has been found to be involved in aspects of appetite and eating, as well as related reward circuitry. Further, they note links between the actions of ghrelin and eating-related stress-induced behaviors. The commentary, uses these two papers as the basis for a wide-ranging discussion of the roles of GLP-1 and ghrelin on energy use; alcohol consumption; and more expansively, reward-based behaviors.
Commentary by Aude Belin-Rauscent, Barry J. Everitt, and David Belin
Corbit LH, Nie H, Janak PH (2012). Habitual alcohol seeking: time course and the contribution of subregions of the dorsal striatum. Biol Psychiatry 72: 389-395.
In this paper, the authors sought to examine the period of time over which use of alcohol switched from a pattern of use that is reliant on outcome, to habitual usage in groups of male Long-Evans rats. They found that while devaluation of ethanol by prior exposure resulted in fewer button presses early in the process of operant training, after eight weeks devaluation no longer resulted in significantly less response. Early in this process, inactivation of the dorsomedial striatum (DMS) attenuated ethanol seeking while inactivation of the dorsolateral striatum (DLS) had no effect. Later however, when rats had become desensitized to ethanol devaluation, this pattern was reversed-ethanol seeking was affected by inactivation of the DLS but not the DMS, suggesting disparate roles for these complementary striatal pathways. The commentary lays out more of the background for this study and summarizes the results in a particularly lucid manner. In addition, some possible physiological underpinnings for these findings are discussed.
Commentary by Charles P. O'Brien
Loland CJ, Mereu M, Okunola OM, et al (2012). R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry 72: 405-413.
In this paper, Dr. Loland and colleagues report that both enantiomers of modafinil bind to the dopamine transporter (DAT) and inhibit dopamine uptake, albeit less strongly than does cocaine; they found that R-modafinil was more potent than S-modafinil. Nonetheless administration of both R- and S-modafinil was associated with increased extracellular dopamine concentrations in the nucleus accumbens. Disparate effects of substituting different strains of DAT mutant mice for wild-type suggest differences in binding sites between the enantiomers. In his commentary, Dr. O'Brien discusses potential clinical implications of these findings.
September 15, 2012
Commentary by Marion Joëls and E. Ronald de Kloet
Bagot RC, Tse YC, Nguyen HB, et al (2012). Maternal care influences hippocampal N-methyl-d-aspartate receptor function and dynamic regulation by corticosterone in adulthood. Biol Psychiatry 72: 491-498.
Previous research has demonstrated wide spread effects of maternal care on hippocampal function in rodents, including effects on the N-methyl-d-aspartate (NMDA) receptor. In this paper, the authors describe the effects of early grooming on NMDA receptor function and expression in adult rats, as well as grooming-related differences in long-term potentiation (LTP). In contrast with studies suggesting that NMDA receptor activity might be decreased with less maternal attention, Dr. Bagot and colleagues found that NMDA receptor expression and function was enhanced in rats who had received less grooming (LG) as pups. These findings were coupled with evidence of decreased LTP. Corticosterone administration raised NMDA receptor activity only in rats who had received more grooming (HG). The authors test their suggestion that this increased NMDA receptor activity in LG rats might be related to decreased LTP in this group-administration of a partial NMDA receptor antagonist did improve LTP in LG rats while impairing LTP in those rats who had received more grooming as pups. In the commentary, these findings are discussed in detail and placed in the context of previous studies of environment-related neuronal plasticity.
Commentary by Neill Epperson and Tracy L. Bale
Bath KG, Chuang J, Spencer-Segal JL, et al (2012). Variant Brain-Derived Neurotrophic Factor (Valine66Methionine) Polymorphism Contributes to Developmental and Estrous Stage-Specific Expression of Anxiety-Like Behavior in Female Mice. Biol Psychiatry 72: 499-504.
Sex differences in mood and anxiety disorders have been well established. In particular, connections have been widely observed between mood and anxiety symptoms, and life-cycle events associated with hormonal changes in women (e.g. menstrual, post-partum, and peri-menopausal periods). In this paper, Dr. Bath and colleagues use a "knock-in" mouse model in which the human brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) was inserted into the BDNF gene, to test the interaction of BDNF changes with hormonal fluctuations. As previously observed, mice with the SNP showed increased anxiety-like behaviors; in addition, these mice exhibited greater anxiety than wild-type mice during the estrous phase, and greater correlation of anxiety-like behaviors with age. While the commentary counsels caution in generalizing these results to human patients, the potential clinical implications of these findings are discussed at length.
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