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A long-standing hypothesis termed "Hebbian plasticity" suggests that memories are formed through strengthening of synaptic connections between neurons with correlated activity. In contrast, other theories propose that coactivation of Hebbian and neuromodulatory processes produce the synaptic strengthening that underlies memory formation. Using optogenetics we directly tested whether Hebbian plasticity alone is both necessary and sufficient to produce physiological changes mediating actual memory formation in behaving animals. Our previous work with this method suggested that Hebbian mechanisms are sufficient to produce aversive associative learning under artificial conditions involving strong, iterative training. Here we systematically tested whether Hebbian mechanisms are necessary and sufficient to produce associative learning under more moderate training conditions that are similar to those that occur in daily life. We measured neural plasticity in the lateral amygdala, a brain region important for associative memory storage about danger. Our findings provide evidence that Hebbian mechanisms are necessary to produce neural plasticity in the lateral amygdala and behavioral memory formation. However, under these conditions Hebbian mechanisms alone were not sufficient to produce these physiological and behavioral effects unless neuromodulatory systems were coactivated. These results provide insight into how aversive experiences trigger memories and suggest that combined Hebbian and neuromodulatory processes interact to engage associative aversive learning.Hebbian plasticity | amygdala | neuromodulation | instructive signals | associative learning H ebbian plasticity refers to the strengthening of a presynaptic input onto a postsynaptic neuron when both pre-and postsynaptic neurons are coactive (1). This was originally proposed as a mechanism for memory formation. Findings from in vitro and in vivo physiological studies suggest that Hebbian processes control synaptic strengthening (2-10). However, other results and theories suggest that Hebbian mechanisms alone are not normally sufficient for producing synaptic plasticity and that synaptic strengthening mediating memory formation involves interactions between Hebbian and neuromodulatory mechanisms (3,4,7,(11)(12)(13)(14)(15)(16)(17)(18)(19). Although molecules that may mediate Hebbian processes in memory formation have been identified (3,11,16,17,(20)(21)(22), it has been difficult to directly test whether Hebbian plasticity alone or in combination with neuromodulation is necessary and sufficient to produce neural plasticity and memories in behaving animals (especially in mammals). This is because of technical limitations in controlling correlated activity between pre-and postsynaptic neurons involved in memory storage in a temporally/spatially precise manner while measuring behavioral memory formation and neural plasticity.To overcome these problems, we used optogenetic techniques to directly manipulate Hebbian mechanisms in pyramidal neurons in the lateral nucl...

Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on β-adrenergic receptors (βARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms. Specifically, using behavioral pharmacology and biochemistry in adult rats, we determined that βAR activity during, but not after PTC training initiates the activation of two plasticity-related targets: AMPA receptors (AMPARs) for memory acquisition and short-term memory and extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory. These findings reveal that βAR activity during, but not following PTC sets in motion cascading molecular events for the acquisition (AMPARs) and subsequent consolidation (ERK) of learned associations.

Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala terazosin delivered before conditioning enhanced short-and long-term memory. Terazosin delivered after conditioning did not affect consolidation. In vitro, terazosin impaired lateral amygdala inhibitory postsynaptic currents leading to facilitation of excitatory postsynaptic currents and long-term potentiation. Since alpha1 blockers are prescribed for hypertension and posttraumatic stress disorder, these results may have important clinical implications.Although norepinephrine (NE) has been widely studied as an important modulator of memory and emotion, comparatively little is known about the role of NE in amygdala-dependent Pavlovian fear conditioning, a major model for understanding the neural basis of fear learning and memory. In fear conditioning, an emotionally neutral conditioned stimulus (CS; i.e., tone) is temporally paired with an aversive unconditioned stimulus (US; i.e., footshock). After very few pairings, a lasting, robust CS-US association is acquired, and the CS elicits stereotypical defensive responses, including behavioral freezing (Blanchard and Blanchard 1969;Bolles and Fanselow 1980). The lateral nucleus of the amygdala (LA) is a key structure underlying fear conditioning (LeDoux 2000). Convergence of CS and US information in LA is believed to play an important role in initiating synaptic plasticity. Long-term potentiation (LTP)-like changes in LA CS processing are critical for fear memory storage (LeDoux 2000;Blair et al. 2001;Maren 2001;Walker and Davis 2002). LA receives auditory CS inputs from the thalamus and cortex and connects directly and indirectly with the central nucleus of the amygdala to control expression of Pavlovian fear responses.Of the noradrenergic receptor subtypes, alpha1 receptors have received the least attention in fear conditioning. LA receives NE-containing inputs from the locus coeruleus that fire tonically and phasically in response to aversive stimuli like footshock (Pitkänen 2000;Tanaka et al. 2000;Aston-Jones and Cohen 2005). Alpha1-adrenergic receptors are expressed in LA, most likely on both excitatory and inhibitory neurons (Jones et al. 1985;Domyancic and Morilak 1997). Alpha1 receptor activation stimulates GABA-mediated miniature inhibitory postsynaptic currents in LA (Braga et al. 2004), suggesting that alpha1 receptors contribute to inhibition in fear conditioning pathways. Several elegant experiments recently demonstrated that LA inhibition gates synaptic plasticity necessary for fear conditioning, and this inhibitory gate can be influenced by neuromodulators including NE (Stutzmann and LeDoux 1999;Shumyatsky et al. 2002;Bissière et al. 2003;Shaban et al. 2006;Shin et al. 2006;Tully et al. 2007). However, the rol...

Pavlovian auditory fear conditioning involves the integration of information about an acoustic conditioned stimulus (CS) and an aversive unconditioned stimulus in the lateral nucleus of the amygdala (LA). The auditory CS reaches the LA subcortically via a direct connection from the auditory thalamus and also from the auditory association cortex itself. How neural modulators, especially those activated during stress, such as norepinephrine (NE), regulate synaptic transmission and plasticity in this network is poorly understood. Here we show that NE inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased toward the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance toward the faster but more primitive subcortical input.