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Anxiety Notes

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Neuronal signaling of Anxiety

How are fear memories represented in the activity of amygdala neurons?
This review considers recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning Studies combining unit recording with brain lesions and pharmacological inactivation provide evidence that the lateral amygdala is a crucial locus of fear memory

Neuronal correlates of aversive memory

Early 1960s - noticed that an auditory stimulus paired with an electric shock modified auditory-evoked field potentials in cats and rats Other investigators observed changes in late components of cortical potentials that were attributed to a general state of fear but these changes were not associative because they occurred in response to both the CS and a novel stimulus Therefore, it became clear that field-potential recordings would not be sufficient to identify loci of fear memory Subsequent single-unit recording studies in cats and monkeys showed conditioning-induced changes in evoked spike activity in several brain areas, including the midbrain, thalamus and cortex. These changes appeared to be associative (Kamikawa 1964) From these studies it was not possible to determine whether structures that showed increased neuronal responsiveness after conditioning were primary sites of plasticity or were downstream from other plastic sites To address this, Olds et al (1972) assessed the latency of conditioned singleunit responses in various brain areas in an appetitive auditory conditioning task They reasoned that structures showing the earliest increases in auditory responses (in terms of ms after CS onset) were probably primary sites of plasticity, whereas those showing longer-latency changes were probably downstream sites that were involved in the expression of learned responses Short-latency plastic responses (within 40ms of tone onset) were observed in the posterior thalamus, medial geniculate nucleus and auditory cortex - indicates that these areas might be primary sites of plasticity Disterhoft et al (1976) confirmed that thalamic plasticity preceded cortical plasticity in terms of both latency and trials. THEREFORE, plasticity in subcortical structures could occur independently of the cortex, and indeed, earning-related plasticity might not even require the forebrain under some circumstances

Fear-related plasticity in the lateral amygdala

Notably absent from these early studies of conditioning was any mention of the amygdala

The thalamus and cortex were thought to be the sites that most probably encode emotional associations, and the amygdala was suspected to have a role in modulating memory storage in these areas HOWEVER, Kapp et al showed that lesions of the central nucleus of the amygdala prevented heart-rate conditioning in rabbits - consistent with central nucleus modulation of fear-expression centres in the midbrain and hypothalamus (1979) Subsequent single-unit recording studies of the central nucleus revealed associative plasticity - indicates that the amygdala might be a site of plasticity in fear conditioning LeDoux et al discovered direct projection from the auditory thalamus to the amydala in rats - determined this projection to be vital for auditory fear conditioning The lateral amygdala (LA) in particular receives direct projection from the medial geniculate nucleus and thalamic posterior intralaminar nucleus (MGm/PIN) Small lesions of the LA or the MGm/PIN prevent fear conditioning, whereas large lesions of the auditory cortex or striatum do not - indicates that thalamoamygdala inputs are sufficient for conditioned fear responses This finding galvanized interest in the L as a potential site of plasticity in fear conditioning Considerable research now indicates that the amygdala is necessary for both the acquisition and expression of Pavlovian fear memories but not for all forms of aversive memory Do neurons in the LA show associative plasticity during fear conditioning?
o Previous work implied the answer was YES but nobody had recorded from the dorsal subdivision (LAd) - primary target of MG,?PIN inputs and a site of CS and US convergence o Quirk et al (1995) recorded Lad neurons in behaving rats and observed robust increases in tone responses during fear conditioning compared with a sensitization control phase. Most of the conditioned increases in spike firing occurred within 15 ms of tone onset - corresponds to the latency of thalamic rather than cortical activation of LA neurons. SHORT-LATENCY PLASTICITY IN LAD o Parallel work has revealed that LA neurons show synaptic LTP (Chapman 1990) and that fear conditioning is associated with LTP-like changes in thalamo-amygdala synaptic transmission o OVERALL, it is therefore thought that the LAd might be a site of long-term memory in fear conditioning It is necessary to show that LAd plasticity is not passively fed forward from either the auditory thalamus or the auditory cortex…
o To determine the contribution of the cortical pathway, Quirk et al compared conditioned unit responses of LAd neurons with those in cortical area Te3 during auditory fear conditioning in rats (1997) (Te3 is the auditory association area that projects to the LAd) o They observed that conditioned plasticity in the Te3 neurons occurred later than in the LAd

o Therefore, plasticity in the LAd is not likely to be fed forward passively from Te3 - it precedes Te3 both within and across trials. It seems unlikely that LA plasticity is passively fed forward form the MGm/PIN - inactivation of the basolateral amygdala (BLA) with the GABA agonist muscimol prevents the acquisition of fear conditioning as well as the expression of fear memory, 24 hours after training when rats are tested drugfree (Muller 1997) THEREFORE, the primary site of plasticity in fear conditioning is unlikely to be the MGm/PIN Maren et al - used muscimol to inactivate the BLA while recording single-unit activity in the MGm/PIN o Prevented the development of conditioned fear AND prevented development of unit plasticity in the MGm/PIN Rather than mirroring thalamic or cortical plasticity, it seems that conditioning-related spike firing in the amygdala is independent of (and maybe essential for) plasticity in the MGm/PIN and Te3

Associative coding in the amygdala

For any conditioning-induced change in neuronal activity, it is essential to determine whether the change is related to the associative learning that encodes the CS-US contingency or whether it represents a non-associative process (a type of learning that does not depend on a CS-US association) that is consequent to either CS or US exposure Changes in behaviour and arousal that accompany learned fear might alter sensory processing in the brain in a way that mirrors associative learning but is not itself the substance of memory Quirk et al 1995 - first study to use single-unit recordings to describe shortlatency plasticity in LA neurons, consistent with potentiation of inputs from the auditory thalamus during fear conditioning o Showed that CS-elicited firing in the LA was greater after CS-US pairing than with an earlier phase of unpaired CS and US presentations o Implies that LA firing is regulated by the associative contingency between the CS and the US o However, it is also possible that shock exposure during conditioning promoted further non-associative sensitization of spike firing to the CS o If so, changes in CS-evoked spike firing after conditioning might have resulted from nonspecific changes in the responsivity of amygdala neurons to any auditory stimulus, rather than an associative change to the specific CS paired with the US To assess this possibility, Paré et al used a discriminative fear-conditioning procedure in conscious cats to determine the specificity of LA plasticity for the auditory CS paired with the US (2000) o 2 distinct cues - a CS+ that was paired with a US, and a CS- that was not o in such a design, differential behaviour to the two CSs is taken as an index of associative learning, and changes in behaviour to the CS-

relative to the pre-conditioning baseline are taken as an index of nonassociative sensitization o found that discriminative fear conditioning produced CS-specific changes in fear behaviour, single units and LFPs in the LA  after fear conditioning, the CS+ evoked a larger LA LFP and more spike firing than it did before conditioning. Conversely, fear conditioning decreased the field potentials and spike firing that were elicited by the CS-. o These changes in CS-elicited neural activity also showed EXTINCTION - returned to baseline levels after several presentations of each CS without the US o Therefore, the increased spike firing in the LA after fear conditioning is CS-specific and cannot be explained by a nonspecific sensitization of spike firing to auditory stimuli or to pseudoconditoning It is necessary to determine whether associative plasticity of CS-elicited LA spike firing is a cause of learned fear responses or a consequence of the behavioural changes that are engendered by the fear state o Examine the development of neuronal plasticity over the course of conditioning - if LA firing codes for fear associations, learning-related activity in the LA should occur BEFORE (or coincident with) the emergence of fear CRs o Repa et al addressed this question (2001) - examined spike firing in the LA during the gradual acquisition of conditioned lever-press suppression o Most of the neurons that were recorded in the LA showed increases in CS-elicited spike firing on or before the trial in which the first significant behavioural CR appeared o Moreover, some LA neurons maintained their conditioning-related increase in spike firing after extinction of the fear response - indicates that the expression of fear behaviour is not driving LA responsiveness. Overall, experiments show that the expression of fear is neither necessary nor sufficient for the expression of associative plasticity in the LA - supports the view that LA neurons encode fear memories The essence of this mnemonic code seems to be contained in the rate at which LA neurons fire APs in response to auditory CSs In addition to this rate code, however, the LA might also signal fear associations by the timing of spikes within a CS-evoked spike train - a rhythm code Fear conditioning has also been shown to increase synchrony in LA neurons - theta oscillations become more frequent in the LA after fear conditioning

Amygdala inhibition after extinction

When signals for aversive events no longer predict those events, fear to those signals subsides This inhibitory learning process (extinction) has important clinical relevance as a treatment for anxiety disorders

The inhibitory memories that are learned during extinction compete with the excitatory memories that are formed during conditioning - suppress fear responses Although fear subsides after extinction, the fear memory is not erased In fact, the inhibitory memories of extinction are relatively short-lived and context-dependent
 biology has deemed it better to fear than not to fear As for fear conditioning, the amygdala appears to have a vital role in the extinction of learned fear Pharmacological manipulations that inhibit neuronal activity or disrupt the cellular processes that underlie synaptic plasticity in the amygdala impair extinction The mediation of extinction by the amygdala is also manifested in the firing of LA neurons. Presenting the CS in the absence of the US reduces the expression of both behavioural CRs and CS-evoked spike firing in most LA neurons However, not all LA neurons reduce their firing after extinction and even neurons that do reduce their firing continue to show the synchrony that is fostered by conditioning How are LA activity and fear expression modulated after extinction?
Recent data indicate an important role for the medial prefrontal cortex (mPFC) Rats with mPFC lesions can learn to extinguish fear CRs but have difficulty recalling the extinction memory 24h after training This is precisely the time when mPFC neurons show robust increases in CSelicited firing - consistent with a role in inhibition of fear after extinction mPFC neurons show an inhibitory influence on both the LA and the central nucleus (main output regions of amygdala) if the inhibitory signal for extinction originates in the mPFC, then it is probably modulated by context one possible modulator of the mPFC is the hippocampus - modulates the expression of extinction memories, according to Concoran (2001) o temporary inactivation of the dorsal hippocampus with muscimol eliminated renewal of fear to an extinguished CS - extinction performance prevailed under conditions in which it would normally be weak o implies that although the hippocampus is not the repository for extinction memories, it is involved in regulating when and where extinction memories are expressed

Conclusions LA neurons seem to be the origin of associative plasticity that is relevant for both learned behavioural responses and physiological plasticity in other brain regions after aversive conditioning Moreover, modulation of the fear-memory code in the LA is involved in the suppression and renewal of fear responses after extinction

The Developmental Origins of Anxiety

In its non-pathological form, anxiety can be divided into two categories o State anxiety - a measure of the immediate/acute level of anxiety o Trait anxiety - reflects the long-term tendency of an individual to show an increased anxiety response In this review, evidence is discussed that supports the idea that increased susceptibility to the expression of anxiety-related behaviour in humans, primates and rodents is the result of abnormal development

Physiology of anxiety

Excessive anxiety has been treated primarily with drugs that have calming properties, including alcohol, barbiturates, opiates, beta-blockers and benzodiazepines Of these, the benzodiazepines are the most specific and effective and are therefore widely used to treat normal and pathological anxiety Benzodiazepines increase the potency of GABA by modulating the function of GABA(A) receptors Based on the effectiveness of GABA enhancing drugs, it has been proposed that excessive excitatory neurotransmission is an important physiological hallmark of anxiety The precise anatomical location and nature of this brain hyperexcitability are not known fMRI studies of humans with anxiety disorders have revealed increased baseline activity in the cingulate cortex and parahippocampal gyrus (Osuch 2000) and increased brain activity in response to anxiety-provoking stimuli in the amygdala, parahippocampal gyrus and frontal cortex Surgical removal of portions of the cingulate cortex is an effective treatment for refractory OCD Together, these studies indicate that the forebrain might be a site of increased excitatory neurotransmission in anxiety disorders Studies of mice with genetically engineered GABA(A) receptors specifically lacking the benzodiazepine-binding site showed that GABA(A) receptors that contain the 2 subunit and that are located in the hippocampus, cortex and amygdala are primarily responsible for the anxiolytic effects of these drugs In the past two decades, another class of drugs, the SSRIs have replaced the benzodiazepines as first-line treatment for anxiety, mostly because they lack the addictive properties of benzodiazepines

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