Anxiety Notes

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 single-unit 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 thalamo-amygdala 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?

  • 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

  • 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

  • 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

  • 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…

  • 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)

  • They observed that conditioned plasticity in the Te3 neurons occurred later than in the LAd

  • 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 drug-free (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...

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