Anxiety and how it works
New Insights Into The Neural Basis Of Anxiety
People who suffer from anxiety tend to interpret ambiguous situations, situations that could potentially be dangerous but not necessarily so, as threatening. Researchers from the Mouse Biology Unit of the European Molecular Biology Laboratory (EMBL) in Italy have now uncovered the neural basis for such anxiety behaviour in mice. In the current issue of Nature Neuroscience they report that a receptor for the messenger serotonin and a neural circuit involving a brain region called the hippocampus play crucial roles in mediating fear responses in ambiguous situations.
A mouse that has learned that a certain cue, for example a tone, is always followed by an electrical shock comes to associate the two and freezes with fear whenever it hears the tone even if the shock is not delivered. But in real life the situation is not always so clear; a stimulus will only sometimes be followed by a threat while other times nothing might happen. Normal mice show less fear towards such ambiguous cues than to clearly threatening stimuli.
A team of researchers led by Cornelius Gross at the EMBL Mouse Biology Unit now discovered that this response to ambiguous stimuli requires a specific receptor molecule for serotonin, a signal many brain cells use to communicate. Mice that lack the serotonin receptor 1A have problems processing ambiguous stimuli and react to them with full-fledged fear responses. The cause is wrongly connected cells in their brains. Serotonin signalling is very important for brain development and if the receptor 1A is missing, defects arise in the wiring of the brain that affect the behaviour of mice later on in life.
“In humans serotonin signalling has been implicated in disorders including depression and anxiety and like our mice patients suffering from these conditions also overreact to ambiguous situations,” Gross says. “The next step was to identify the brain regions that are responsible for such complex fear behaviour and the processing of ambiguous cues.”
Using a new technique to switch off neural activity in selective brain cells in living mice, Gross and his colleagues discovered that a specific part of the hippocampus is required for correct processing of ambiguous stimuli.
“Shutting down a specific circuit in the hippocampus abolished fear reactions only to ambiguous cues,” says Theodoros Tsetsenis who carried out the research in Gross’ lab. “The pathway must be involved in processing and assessing the value of stimuli. It seems to bias mice to interpret situations as threatening.”
The hippocampus is mainly known as a region important for learning and memory, but the results reveal a more general role in evaluating information and assessing contingencies.
Neural circuits that govern fundamental behaviours like fear are often often conserved between species and patient studies suggest a role for the hippocampus in anxiety also in humans.
The new insights gained into serotonin signalling via the receptor 1A and the role of the hippocampus in fear behaviour in mice promise to shed light on the neural basis of anxiety disorders and open up new avenues for therapies. Nonetheless, these results do not overlap with the recently discovered difference between anxious apprehension (verbal rumination, worry) and anxious arousal (intense fear, panic, or both). https://huehueteotl.wordpress.com/2007/05/30/worry-is-not-the-same-as-fear/ shows different areas of brain activation, using fMRT in human subjects. A mouse model is anyway hardly likely to tell the difference between fear and worry, if philosophically speaking, one does admit apprehension in non-human mammal behaviour at all.
nature neuroscience online: 3 June 2007; | doi:10.1038/nn1919
Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus
Theodoros Tsetsenis1, Xiao-Hong Ma2, Luisa Lo Iacono1, Sheryl G Beck2 & Cornelius Gross1
1 European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Via Ramarini 32, 00015 Monterotondo, Italy.
2 Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, Pennsylvania 19104, USA.
Serotonin receptor 1A knockout (Htr1aKO) mice show increased anxiety-related behavior in tests measuring innate avoidance. Here we demonstrate that Htr1aKO mice show enhanced fear conditioning to ambiguous conditioned stimuli, a hallmark of human anxiety. To examine the involvement of specific forebrain circuits in this phenotype, we developed a pharmacogenetic technique for the rapid tissue- and cell type–specific silencing of neural activity in vivo. Inhibition of neurons in the central nucleus of the amygdala suppressed conditioned responses to both ambiguous and nonambiguous cues. In contrast, inhibition of hippocampal dentate gyrus granule cells selectively suppressed conditioned responses to ambiguous cues and reversed the knockout phenotype. These data demonstrate that Htr1aKO mice have a bias in the processing of threatening cues that is moderated by hippocampal mossy-fiber circuits, and suggest that the hippocampus is important in the response to ambiguous aversive stimuli.
Neuropsychopharmacology. 2006 Jan;31(1):101-11.
Increased fear response to contextual cues in mice lacking the 5-HT1A receptor.
Klemenhagen KC, Gordon JA, David DJ, Hen R, Gross CT.
Center for Neurobiology and Behavior, Columbia University, New York, NY 10032-2695, USA.
Serotonin 1A receptor knockout (5-HT1AR KO) mice exhibit increased behavioral inhibition in conflict tests. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests. First, we considered whether behavioral inhibition in these knockout mice is a consequence of reduced exploratory motivation. The knockout mice engage in normal exploration during a light-dark test and normal exploration of a novel object in a familiar environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Second, we tested whether these mice exhibit increased behavioral inhibition in response to any aversive cues, or whether this response depends on cue modality. Knockout mice respond normally to discrete aversive cues in the Vogel lick-suppression test, arguing that their phenotype is restricted to conflict tests based on complex or spatial aversive cues. Third, to probe the processing of spatial aversive cues, we assessed fear conditioning to contextual cues. After contextual fear conditioning, knockout and wild-type (WT) mice express freezing responses when exposed to the training environment. However, when placed in an ambiguous environment containing both conditioned and novel cues, the freezing response of knockout mice does not significantly decrease as it does in WT mice, suggesting that the knockout fear response is biased toward threatening cues. We hypothesize that this inappropriate generalization of fearful behavior to a context containing both fearful and neutral stimuli, a phenomenon that occurs in a subset of human anxiety disorders such as panic disorder and post-traumatic stress disorder, underlies the anxiety phenotype of 5-HT1AR KO mice. Neuropsychopharmacology (2006) 31, 101-111. doi:10.1038/sj.npp.1300774; published online 25 May 2005.