Anxiety Flashcards
Baxter 2013
First SR to report worldwide prevalence of anxiety disorders - studies across 44 countries, 1/14 around world at any given time had an anxiety disorder. ~1/9 people will have an anxiety disorder in any given year. Women 2x more likely than men to have anxiety disorder. General phobias are the most common type of anxiety disorder, second most common = SAD. However, clinical diagnosis = overlapping so difficult to say.
LeDoux et al 1990
Rats subjected to classical conditioning trials, the CS was a sound wave and the US was an electrical shock - they electrolytically lesioned the lateral amygdala of rats - in sham-lesioned controls, the CS evoked stereotyped increased in blood pression and freezing behaviour - in lesioned, found response to CS, the pressor and freezing responses were both greatly reduced (although study is old so no statistical comparisonl - They concluded - the lateral amyg was a sensory interface for this CS-US association forming
Etkin et al 2012
Meta-analysis of PET and fMRI imaging of PTSD, social anxiety dis and phobias - overall analyzed data from 19 comparisons in PTSD, 11 in social anxiety disorder, and 10 in specific phobia - increased amygdala activation compared to controls. However, they also observed consistent amygdala activation during fear conditioning in healthy subjects - conclude that amygdala hyperactivation in PTSD, social anxiety disorder and specific phobia reflects a common exaggerated engagement of fear circuitry, which results in shared symptoms among the disorders
Johansen et al 2010
- Expressed ChR2 in lateral amygdala pyramidal cells in mice using a viral targetting technique
- This allowed optical control of LA neuronal activity.
- They then paired an auditory sensory cue (tone) with optical stimulation of LA pyramidal neurons (flash of light) instead of an aversive stimullius.
- Subsequently, presenting the tone alone produced behavioural fear responses
- Limitation - Activating whole population of neurons in LA may render precision obsolete and could be having off-target effects (we might be simplifying too much), more specific cell targetting is required to see the full effects of fear conditioning. A number of studies have found that separate populations of amygdala nueorns mediate aversive and appetitive processing. Thus, separate intermixed populations of amygdala nueorons are likely to participate in producing different behaviural responses (i.e aversively vs appetitively motivated). The laser condition coudl have induced plasticity indiscriminately in both cell populations and this may have interfered with the freezing response
- What else? Although stimulation of LA neurons supported fear learning, freezing scores during the long-term memory test were relatively low compared with those obtained with an electric shock US. Why? Maybe plasticity in other parts of circuit required? See above where the appetitively involved circuits could have interfered? Also, maybe coactivation of other neuromodulatory systems is required?
Goosens and Maren 2004
- Injected NMDAR antagonist CPP prior to the conditioning.
- Did Pavlovian fear conditioning. Administered CPP prior to auditory fear conditioning which completely abolished the acquisition of conditional freezing and conditional single-unit activity in the LA (measured my multichannel recording electrodes aimed at the LA).
- Administration of CPP also blcoked induction of LTP in the amygdala of anesethised rats.
- This suggests that NMDARs are essention for aquisition of conditioning-related plasticity in the amygdala
- Limitation They administered CPP systematically - other NMDA antagonists produce marked alterations in behaviour (they even observed mild ataxia) + did not look at LTP and conditioning induced changes in spike firing in the same regions (LTP in basal amygdal and spike firing in lateral amygdala)
Ciocchi et al 2010
Mice were trained in a fear conditioning paradigm and froze when presented with conditioned stimulus. Regarding conditioned fear - when muscimol-BPY was applied during fear conditioning, inactivation of the whole CEA and CEl lead to decereased freezing, but freezing was still present when CEm was inactivated. However, when muscimol-BPY was applied 24h after conditioning, inactivation of the CEm, but not the CEl, reduced conditioned freezing response. Shows that the CEA is important but there is a functional dissociation between CEl and CEm during aquisition and expession of conditioned fear response. Highlights complexity of the system
Milad et al 2002
They knew that destruction of the central medial PFC, consisting of infralimib and prelimbic cortices, blcoks recall of fear extinction. Rats did Pavlovian fear conditioning. In the conditioning phase tones were paired with foot shock, and then 1h later, they go tones without foot shock (extinction phase). The next day they were given additional tones to test for recall of extinction learning. They did single-unit recording of neurons from the mPFC (infralimbic cortex, prelimbic cortex or medial orbital cortex). They show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least during recall showed the greatest increase in infralimbic tone responses. This suggests that enhanced IL tone is responsible for suppression of freezing during extinction.
Herry et al 2008
- Took mice and performed in vivo single-unit recordings from amygdala.
- Did Pavlovian fear conditioning. One sound (CS+) was paired with shock (US), while another (US-) wasn’t.
- In agreement with previous work…Put probe in BLA and demonstrated pairing of CS and US enhanced firing in a population of BLA neurons in response to CS alone. Called them ‘fear neurons’.
- But intriguingly, when they then put these mice through fear extinction, these neurons stopped firing – interestingly another population of neurons in BLA increased in firing – they called these ‘extinction neurons’.
- Finally, (this is RENEWAL) when the mice moved from extinction context back to conditioning context, fear responses returned phenotypically.
- Fear neurons fire again and extinction neurons stop firing.
- These changes occurred before the onset of any behavioural response, suggesting they are what controls the behavioural response.
- They then used extracellular stimulation in anaesthetized mice to identify orthodromic and antidromic connections between BA neurons and the mPFC and hippocampus.
- Found that fear neurons have input from hippocampus while extinction neurons have reciprocal connections with PFC
- Limitations. C57B1/6 mice - inbred strain + problems with extrapolation to humans etc. Did not test the casual lin between activity and behaviour - only correlative. Could have supplemented orthodromic and antidromic stimulation with flourescent labelling
Chavanne and Robinson 2021
Meta-analysis Had 156 studies and a wide range of different anxiety/anxiety-related disorders. Show that clinical anxiety is associated with heightened activity in several regions - incl amygdala, anterior hippocampus, PAG, stria terminalis (only recently begun to draw attention of psychiatric community), dorsolateral PFC, ACC and anterior insula. These replicate Etkin’s meta-analysis.
Malizia 1998
Used PET w the radioligand 11[C]-flumazenil to label the benzo site on the GABA(A) receptor. Compared 7 pts with panic disorder and 8 healthy controls. Found global reduction in the benzodiazepine site binding throughout the brain in pts with panic disorder. Strengthens the case that abnormalities in basal or adaptive inhibitory neuromodulation are of pathologic significance in this condition
Heldt (2012)
Used lentiviral-based RNAi strategy - wanted to KO GAD-67 in the BLA. GAD67 is involved in GABA synthesis so this knocks down GABA expression in the BLA. They gave mice nilateral amygdala microinjections of this siRNA. Behavioural experiments showed that this resulted in a deficient of extinction, but not aquisition of fear, as measured by conditional freezing. Suggests GABAergic transmission in amygdala mediated inhibition of conditioned fear.
McKernan (2000)
Generated transgenic mouse w single aa substitution in the alpha 1 subunit - all GABA-A Rs with this subunit were now insensitive to BZDs. They found sedation was not induced by diazepam in these mice, but the anxiolytic effects still remained. Caveat - they measured sedation via reduction in motor activity - maybe there was some kind of motor impairment instead, rather than sedation. They also took normal mice and used a compound that was a partial agonist of alpha 2,3,5, and antagonist at alpha 1 - anxiolysis was retained by motor activity was not reduced - another way of showing the same thing. Idea - protect alpha 1 (dont get drowsy) but target the remaining subunits to get anxiolytic effects
Dias et al 2005
Administration of TP003 to rats produced no significant difference in rotarod performance, but induced anxiolyic effects in the elevated plus maze (more time spent in open arms) - so anxiolytic with no motor impairment
Rupprecht et al 2009
Examined the effects of XBD173 which acts as an agonist at TSPO. “o In mouse neocortical slices it potentiated GABAergic transmission; this was prevented by the 5alpha-reductase inhibitor finasteride, showing that this effect was dependent on steroidogenesis. o XBD173 counteracted lactate-induced panic reactions in rats (social interaction times were significantly greater and freezing was significantly reduced compared to controls). o Chronic treatment also failed to induce sedation, indicating that XBD173s effects are anxiolytic-specific. o The drug was also found to suppress panic anxiety induced by CCK4 administration in humans. Limitations - Only one paradigm (CCK4 challenge) was used in humans, which is not reflective of the heterogeneity of anxiety pathology, and XBD was not tested on pts with anxiety disorders. Also CCK$ is rapidly broken down in the body and so only has a short duration of action.
Han et al 2019
SHISA7 is localised to GABAergic synapses. SHISA7 was overexpressed in hippocampal neurons colocalised with GABAaRs (shown using an immunocytochemical assay and super-resolution microscopy analysis) They find that in mice in which Shisa7 was ablated, GABAa receptor abundance and channel deactivation kinetics were decreased. The authors evaluated how that lack of SHISA7 expression affects the behavioural response to benzos. Diazepam reduced locomotor actvity, which is indicative of a sedative action, in WT mice but not in mice lacking Shisa7. Furthermore, diazepam displayed an anxiolytic-like action (elevated plus maze)in WT mice but not in mice lacking Shisa7. Because the reduction of motor activity by diazepam has been shown to be mediated by alpha1-containing GABAa receptors and the reduction of anxietgy to be mediated by alpha2-containing GABAa receptors, the results indicate that SHISA7 is required for modulation of these receptor subtypes by diazepam. This identifies SHISA7 as a thus far unrecognisied essential component required for modulation of these receptor subtypes by benzodiazepmines. Criticism Han et al call it an auxiliary subunit - this is confusing bc it suggests it is an essential component but there are only modest effects of Shisa7 inactivation
