Hebbian and neuromodulatory mechanisms interact to trigger associative memory formation

Abstract

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...

Fear Memory

“…There was a dispute in the late 1990s about whether the BLA was involved (165) or not (640) in memory consolidation of CFC. Most current accounts favor the view that LTP in auditory afferents to the LA are critically involved in this (295,296,448,591), but still many recent studies endorse the view of a crucial cognitive involvement of the BLA in the making of conditioned fear (102, 189), and others favor the idea that the BLA processes the storage of IA in parallel to the hippocampus (63, 107, 273, 291) (see below).…”

“…Johansen et al (295) found that both the Hebbian rule viewed by many as the golden rule of conditioning ("a synaptic input is strengthened when activity in the presynaptic neuron co-occurs with excitatory activity in the postsynaptic neuron") and modulatory influences must converge on…”

“…(54) showed a posttraining role of the BLA in object recognition memory, a type of learning commonly attributed to the hippocampus and cortical temporal areas, but usually not to the amygdala (96,125). Optogenetic methods have demonstrated the participation of LA neurons in fear conditioning (295). In all probability, different neurons participate in each of these activities (see sect.…”

“…Nowadays hippocampus and amygdala are both viewed as important for the processing of many types of information, and in particular for memory consolidation in the first few hours after acquisition (125,226,265,272,401,403,657). Fear conditioning in particular relies on CS-US interactions in the DG and in the LA (295,328,350,448,574). After all, this fits better with the findings on humans with large bilateral temporal lobe lesions (493,589), specifically those with lesions restricted to the hippocampus (308,549,664,686), who have consistently been shown to have a general incapacity to retain new declarative memories of any kind, but to remember well memories acquired weeks or months before the lesion, and, importantly, do not show appreciable deficits in scene construction (of a picture they see) while consistently losing memory items relevant to that scene (308).…”

“…Recent evidence (295) indicates that the two roles may converge in the case of fear memories, and that the latter appears to be restricted to the LA and is mediated by LTP generated at the synapses of auditory pathways on LA cells, as shown by Rogan et al (538) and by McKernan and Shinnick-Gallagher in 1997 (411) and more recently (2014) by Nabavi et al (448) and Johansen et al (295). NE upregulates hippocampal LTP via ␤ receptors, a function which can be disrupted by stress (220,221), along with hippocampus-based memories.…”