Fear becomes first emotion to yield to molecular neuroscience
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For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Neurology Vol 1 September 2002 http://neurology.thelancet.com 273 Newsdesk results reported by Rothwell and Levison may simply reflect the different outcome parameters used by the two groups. Nevertheless, for now Rothwell cautions against looking for molecules targeted specifically at IL-1R1 for therapeutic use and notes that she is initiating early clinical trials of an IL-1 blocker. Levison agrees that it will be important to know more about potential additional receptors before going down the IL-1R1 route, but notes that “targeting IL-1 itself, as well as damping down the inflammatory response, would also remove adaptive effects of IL-1 such as induction of nerve growth factor, which did not require IL-1R1 in our experiments”. Jane Bradbury Mounting evidence indicates that interleukin-1 (IL-1) is involved in the development of brain damage after injury. Now, Anirban Basu and colleagues (Pennsylvania State University College of Medicine, Hershey, PA, USA) report that the type 1 IL-1 receptor (IL-1R1) is necessary for the activation of micro- glia and induction of proinflam- matory mediators in response to a penetrating brain injury. “On the basis of our results”, says senior researcher Steven Levison, “we believe that IL-1R1 could be a key drug target for reduction of brain damage after injury.” IL-1 concentrations in brain are normally low. However, in response to experimental or clinical insults such as traumatic brain injury and stroke, IL-1 brain concentrations increase. 10 years ago, Nancy Rothwell (University of Manchester, UK) showed that treatment with a naturally occuring IL-1 receptor antagonist prevented neuronal death in a rat model of ischaemia. Since then, much has been learnt about IL-1, but how blocking IL-1 action provides neuroprotection remains unclear. To discover more, Levison’s team looked at cellular and molecular responses to penetrating brain injury in wild-type mice and mice null for IL-1R1. Fewer microglia and macrophages collected next to damaged tissue in IL-1R1-null mice, and expression of the proinflam- matory mediators cyclooxygenase 2 and IL-6 was reduced in the null mice compared with the wild-type mice (J Neurosci 2002: 22: 6071–82). The team now plans to look at a stroke model in the two types of mice, and, says Levison, “I predict that we will get similar results”. “This is a nicely done paper”, says Rothwell, “that once again shows the importance of IL-1 in the inflam- matory response to brain injury. However, we recently reported that the IL-1R1-null mice do not have a reduced response to ischaemic brain damage (J Neurosci 2002; 22: 38–43) and suggested that there might be additional IL-1 receptors in the brain.” The apparently contradictory The IL-1 type 1 receptor: a drug target for treating brain injury? Fear becomes first emotion to yield to molecular neuroscience Individual genes can influence how we feel about our environment, according to research published in July. “Our data are the first demonstration of a mechanism by which a gene can affect the function of a system in the brain involved in emotional processing”, notes lead researcher Daniel Weinberger (National Institute on Mental Health, Bethesda, MD, USA). The group is exploring the genetic architecture of fear processing by studying links between single-gene variants and the responsiveness of the amygdala, a region involved in experience of fear. Their recent Science publication further implicates polymorphisms in the serotonin transporter (5-HTT) gene as a likely key factor in the complex interplay of anxiogenic and anxiolytic processes that results in individual anxiety states (Science 2002; 297: 400–03). The 5-HTT gene has either a long (l) or short (s) promoter region, and individuals with one or two s alleles have an increased risk of various psychological and behavioural traits, such as neuroticism and alcohol abuse. However, studies attempting to relate gene variants to anxiety disorders have produced conflicting results. Weinberger’s team hypothesised that a direct assay of brain activity might highlight differences between people with an s allele (group S) and those without (group L). So they investigated the response of amygdala activity to facial-emotion processing tasks, using functional magnetic resonance imaging to measure local blood-oxygen level. Group S was more responsive to fearful stimuli, most likely reflecting increased neuronal excitability, the team speculate, although they have not yet proven that this is linked with increased synaptic serotonin. Anxiety has been linked with several neurotransmitter systems, although most experts agree that serotonin plays a central role. “While a single gene cannot be held accountable for complex emotional states, such as anxiety disorders, we’re beginning to pinpoint which genetic traits may make a person susceptible to developing psychological disorders”, says Norman Schmidt of Ohio State University, USA. According to Schmidt, most experts believe fear and anxiety are regulated by “quite a few genes. Until we can adequately model more complex gene interactions, it’s unlikely that we will be able to tell the complete story”. The Weinberger team’s findings may help resolve some contradictory findings, such as those previously reported by Schmidt’s team, which showed increased misperception of physical symptoms as anxiety in l carriers, especially in those who also had the psychological trait of anxiety sensitivity. Schmidt concludes from “converging lines of evidence” that “adults with anxiety disorders may have an underlying constitutional vulnerability that is partly genetic and variably expressed over time”. Kelly Morris
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Transcript of Fear becomes first emotion to yield to molecular neuroscience
For personal use. Only reproduce with permission from The Lancet Publishing Group.
THE LANCET Neurology Vol 1 September 2002 http://neurology.thelancet.com 273
Newsdesk
results reported by Rothwell andLevison may simply reflect thedifferent outcome parameters used bythe two groups. Nevertheless, for nowRothwell cautions against looking formolecules targeted specifically at IL-1R1 for therapeutic use and notesthat she is initiating early clinical trialsof an IL-1 blocker. Levison agrees thatit will be important to know more
about potential additional receptorsbefore going down the IL-1R1 route,but notes that “targeting IL-1 itself, aswell as damping down theinflammatory response, would alsoremove adaptive effects of IL-1 such asinduction of nerve growth factor,which did not require IL-1R1 in ourexperiments”.Jane Bradbury
Mounting evidence indicates thatinterleukin-1 (IL-1) is involved in thedevelopment of brain damage afterinjury. Now, Anirban Basu andcolleagues (Pennsylvania StateUniversity College of Medicine,Hershey, PA, USA) report that thetype 1 IL-1 receptor (IL-1R1) isnecessary for the activation of micro-glia and induction of proinflam-matory mediators in response to apenetrating brain injury. “On thebasis of our results”, says seniorresearcher Steven Levison, “we believethat IL-1R1 could be a key drug targetfor reduction of brain damage afterinjury.”
IL-1 concentrations in brain arenormally low. However, in responseto experimental or clinical insults suchas traumatic brain injury and stroke,IL-1 brain concentrations increase. 10years ago, Nancy Rothwell (Universityof Manchester, UK) showed thattreatment with a naturally occuring IL-1 receptor antagonist preventedneuronal death in a rat model ofischaemia. Since then, much has beenlearnt about IL-1, but how blockingIL-1 action provides neuroprotectionremains unclear.
To discover more, Levison’s teamlooked at cellular and molecularresponses to penetrating brain injuryin wild-type mice and mice null for IL-1R1. Fewer microglia andmacrophages collected next todamaged tissue in IL-1R1-null mice,and expression of the proinflam-matory mediators cyclooxygenase 2and IL-6 was reduced in the null micecompared with the wild-type mice (J Neurosci 2002: 22: 6071–82). Theteam now plans to look at a strokemodel in the two types of mice, and,says Levison, “I predict that we will getsimilar results”.
“This is a nicely done paper”, saysRothwell, “that once again shows theimportance of IL-1 in the inflam-matory response to brain injury.However, we recently reported thatthe IL-1R1-null mice do not have areduced response to ischaemic braindamage (J Neurosci 2002; 22: 38–43)and suggested that there might beadditional IL-1 receptors in thebrain.” The apparently contradictory
The IL-1 type 1 receptor: a drug target for treating brain injury?
Fear becomes first emotion to yield tomolecular neuroscienceIndividual genes can influence howwe feel about our environment,according to research published inJuly. “Our data are the firstdemonstration of a mechanism bywhich a gene can affect the functionof a system in the brain involved inemotional processing”, notes leadresearcher Daniel Weinberger(National Institute on Mental Health,Bethesda, MD, USA).
The group is exploring the geneticarchitecture of fear processing bystudying links between single-genevariants and the responsiveness of theamygdala, a region involved inexperience of fear. Their recentScience publication further implicatespolymorphisms in the serotonintransporter (5-HTT) gene as a likelykey factor in the complex interplay ofanxiogenic and anxiolytic processesthat results in individual anxietystates (Science 2002; 297: 400–03).
The 5-HTT gene has either a long(l) or short (s) promoter region, andindividuals with one or two s alleleshave an increased risk of variouspsychological and behavioural traits,such as neuroticism and alcoholabuse. However, studies attemptingto relate gene variants to anxietydisorders have produced conflictingresults.
Weinberger’s team hypothesisedthat a direct assay of brain activitymight highlight differences betweenpeople with an s allele (group S) andthose without (group L). So theyinvestigated the response of amygdalaactivity to facial-emotion processingtasks, using functional magnetic
resonance imaging to measure localblood-oxygen level. Group S wasmore responsive to fearful stimuli,most likely reflecting increasedneuronal excitability, the teamspeculate, although they have not yetproven that this is linked withincreased synaptic serotonin.
Anxiety has been linked withseveral neurotransmitter systems,although most experts agree thatserotonin plays a central role. “Whilea single gene cannot be heldaccountable for complex emotionalstates, such as anxiety disorders,we’re beginning to pinpoint whichgenetic traits may make a person susceptible to developingpsychological disorders”, saysNorman Schmidt of Ohio StateUniversity, USA. According toSchmidt, most experts believe fearand anxiety are regulated by “quite afew genes. Until we can adequatelymodel more complex geneinteractions, it’s unlikely that we willbe able to tell the complete story”.
The Weinberger team’s findingsmay help resolve some contradictoryfindings, such as those previouslyreported by Schmidt’s team, whichshowed increased misperception ofphysical symptoms as anxiety inl carriers, especially in those who alsohad the psychological trait of anxietysensitivity. Schmidt concludes from“converging lines of evidence” that“adults with anxiety disorders mayhave an underlying constitutionalvulnerability that is partly genetic andvariably expressed over time”.Kelly Morris
