Multivariate FMRI Signatures of Learning in a Hebb Repetition Paradigm With Tone Sequences

Important information from the environment often arrives to the brain in temporally extended sequences. Language, music, actions, and complex events generally unfold over time. When such informational sequences exceed the limited capacity of working memory, the human brain relies on its ability to accumulate information in long-term memory over several encounters with a complex stimulus. A longstanding question in psychology and neuroscience is whether the neural structures associated with working memory storage—often viewed as capacity limited and temporary—have any builtin ability to store information across longer temporal delays. According to the classic Hebbian dual memory theory, temporally local “activity traces” underlie immediate perception and working memory, whereas “structural traces” undergird long-term learning. Here we examine whether brain structures known to be involved in working maintenance of auditory sequences, such as area Spt, also show evidence of memory persistence across trials. We used representational similarity analysis (RSA) and the Hebb repetition paradigm with supracapacity tonal sequences to test whether repeated sequences have distinguishable multivoxel activity patterns in the auditory-motor networks of the brain. We found that, indeed, area Spt and other nodes of the auditory dorsal stream show multivoxel patterns for tone sequences that become gradually more distinct with repetition during working memory for supracapacity tone-sequences. The findings suggest that the structures are important for working memory are not “blank slates,” wiped clean from moment to moment, but rather encode information in a way can lead to cross-trial persistence.

Developmental emergence of persistent memory for contextual and auditory fear in mice

The ability to generate memories that persist throughout a lifetime (that is, memory persistence) emerges in early development across species. Although it has been shown that persistent fear memories emerge between late infancy and adolescence in mice, it is unclear exactly when this transition takes place, and whether two major fear conditioning tasks, contextual and auditory fear, share the same time line of developmental onset. Here, we compared the ontogeny of remote contextual and auditory fear in C57BL/6J mice across early life. Mice at postnatal day (P)15, 21, 25, 28, and 30 underwent either contextual or auditory fear training and were tested for fear retrieval 1 or 30 d later. We found that mice displayed 30-d memory for context– and tone–fear starting at P25. We did not find sex differences in the ontogeny of either type of fear memory. Furthermore, 30-d contextual fear retrieval led to an increase in the number of c-Fos positive cells in the prelimbic region of the prefrontal cortex only at an age in which the contextual fear memory was successfully retrieved. These data delineate a precise time line for the emergence of persistent contextual and auditory fear memories in mice and suggest that the prelimbic cortex is only recruited for remote memory recall upon the onset of memory persistence.

Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism

Peripheral inputs to the brain continuously shape its function and adjust non-emotional memory, but the mechanisms involved are not fully understood. Cannabinoid type-1 receptors (CB1Rs), widely distributed in the organism, are well recognized players in memory performance and their systemic modulation significantly influence memory function. By assessing non-emotional memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, peripherally restricted CB1R antagonist AM6545 showed a mnemonic effect occluded in adrenalectomized mice, after peripheral adrenergic blockade, or when vagus nerve was chemogenetically inhibited. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced memory persistence, supporting a role of peripheral CB1Rs modulating the adrenergic tone. Notably, while brain connectivity was slightly affected by peripheral CB1R inhibition, locus coeruleus activity and extracellular norepinephrine in the hippocampus, were increased, and intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Together, we disclose a novel peripheral mechanism relevant for non-emotional memory persistence modulation.

A Synaptic Framework for the Persistence of Memory Engrams

The ability to store and retrieve learned information over prolonged periods of time is an essential and intriguing property of the brain. Insight into the neurobiological mechanisms that underlie memory consolidation is of utmost importance for our understanding of memory persistence and how this is affected in memory disorders. Recent evidence indicates that a given memory is encoded by sparsely distributed neurons that become highly activated during learning, so-called engram cells. Research by us and others confirms the persistent nature of cortical engram cells by showing that these neurons are required for memory expression up to at least 1 month after they were activated during learning. Strengthened synaptic connectivity between engram cells is thought to ensure reactivation of the engram cell network during retrieval. However, given the continuous integration of new information into existing neuronal circuits and the relatively rapid turnover rate of synaptic proteins, it is unclear whether a lasting learning-induced increase in synaptic connectivity is mediated by stable synapses or by continuous dynamic turnover of synapses of the engram cell network. Here, we first discuss evidence for the persistence of engram cells and memory-relevant adaptations in synaptic plasticity, and then propose models of synaptic adaptations and molecular mechanisms that may support memory persistence through the maintenance of enhanced synaptic connectivity within an engram cell network.