Lecture 9 Memory circuitry: The amygdala and fear conditioning; memory allocation

Recommended reading

1: Reijmers LG, Perkins BL, Matsuo N, Mayford M. Localization of a stable neural correlate of associative memory. Science. 2007 Aug 31;317(5842):1230-3. 2: Guzowski JF, Setlow B, Wagner EK, McGaugh JL. Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, cfos, and zif268. J Neurosci. 2001 Jul 15;21(14):5089-98. 3: Han JH, Kushner SA, Yiu AP, Cole CJ, Matynia A, Brown RA, Neve RL, GuzowskiJF, Silva AJ, Josselyn SA. Neuronal competition and selection during memory formation. Science. 2007 Apr 20;316(5823):457-60. 4: Han JH, Kushner SA, Yiu AP, Hsiang HL, Buch T, Waisman A, Bontempi B, Neve RL, Frankland PW, Josselyn SA. Selective erasure of a fear memory. Science. 2009 Mar 13;323(5920):1492-6.

Fear conditioning is an implicit memory and can become recallable with medial temporal lobe involvement

Implicit Memory: Fear Conditioning

TRAINING

Animal is placed in novel context Hears a tone Receives foot shock CONTEXTUAL TEST CUED TEST

Animal is returned to same context Test for freezing behavior

Animal is placed in modified context Hears a tone Test for freezing behavior

Figure 8: Auditory fear conditioning pathways. The auditory conditioned stimulus (CS) and somatosensory (pain) unconditioned stimulus (US) converge in the lateral amygdala (LA). The LA receives inputs from each system via both thalamic and cortical inputs. CSUS convergence induces synaptic plasticity in LA such that after conditioning the CS flows through the LA to activate the central amygdala (CE) via intraamygdala connections. CE in turn controls the expression of behavioral (freezing), autonomic and endocrine responses that are components of the fear reaction. Other abbreviations: B, basal amygdala; CG, central gray; LH, lateral hypothalamus; ITC, intercalated cells of the amygdala; PVN, paraventricular nucleus of the hypothalamus

In the mammalian brain there is a distinct ensemble of neurons that code for a particular memory.
How can the ensemble be identified?

Immediate early genes as markers of neuronal activity

Guzowski, J. F. et al. J. Neurosci. 2001;21:5089-5098

Copyright 2001 Society for Neuroscience

Figure 3.

Guzowski, J. F. et al. J. Neurosci. 2001;21:5089-5098

Immediate early genes and synaptic plasticity

The zif-268 (egf-1) gene and fos gene encode transcription factors with binding sites on the promoters of hundreds of different genes IEGs are induced by high-frequency stimulation that triggers hippocampal longterm potentiation (LTP), a leading model of synaptic plasticity thought to underlie memory formation (Bliss and Lmo 1973; Bliss and Collingridge 1993). Most importantly, their expression is actually required for the long-term maintenance of hippocampal LTP, as well as spatial and nonspatial long-term memories.

Arc mRNA is transported to dendrites and translated in dentritic spines

Arc is transported to dendrites and can be targeted to stimulated synaptic areas

Bramham et al., 2010

The transport of arc mRNA allows for measurements of neuronal activation at two time points

arc red zif - green

A/B delay: 5 min exposure to environment A 20 min delay 5 min exposure to B 25 min delay

Fig. 1. (A) Tagging of activated neurons is achieved by two transgenes present in the TetTag mouse

Fos-prom

Fos

L. G. Reijmers et al., Science 317, 1230 -1233 (2007)

tTA tetracycline transactivator tTA* - Dox-insensitive tTA

Published by AAAS

Fig. 2. (A) A protocol was designed to detect repeated activation of neurons during learning and retrieval of conditioned fear

L. G. Reijmers et al., Science 317, 1230 -1233 (2007)

Published by AAAS

Fig. 3. Reactivated neurons in the BLA during fear conditioning provide a stable neural correlate of associative memory

LAC

ZIF

L. G. Reijmers et al., Science 317, 1230 -1233 (2007)

Published by AAAS

Fig. 1. Auditory fear conditioning activates CREB in ~20% of LA cells in wild-type (WT) mice; increasing CREB function in a similar portion of LA neurons rescues the fear memory deficit in CREB-deficient mice

J.-H. Han et al., Science 316, 457 -460 (2007)

Published by AAAS

Fig. 2. Neurons with increased CREB function are more likely than their neighbors to be recruited to the fear memory trace

J.-H. Han et al., Science 316, 457 -460 (2007)

Published by AAAS

Reijmers and Mayford, 2009; Frontiers in Molecular Neuroscience 2,1-8

Fig. 2. Neurons overexpressing CREB preferentially activated by fear memory testing

J.-H. Han et al., Science 323, 1492 -1496 (2009)

Published by AAAS

Fig. 3. Overexpressing CREB in LA neurons enhances memory induced by weak training; subsequent ablation of these neurons reverses this enhancement

J.-H. Han et al., Science 323, 1492 -1496 (2009)

Published by AAAS

Fear conditioning

Fear conditioning