Neuronal Allocation to a Hippocampal Engram

Abstract

The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron's excitability. Here, we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, whereas silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation.

Induction of activity synchronization among primed hippocampal neurons out of random dynamics is key for trace memory formation and retrieval

“…However, it remains to be determined how Silent Neurons get primed. Hypothetically, elevated CREB expression may increase the excitability and promote the priming of Silent Neurons …”

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

“…These results demonstrate that relative CREB levels can affect which neurons are incorporated into a memory trace, a phenomenon referred to as memory allocation. Subsequent studies showed that inhibition of CREB-overexpressing cells negatively affects memory recall 31,33–35 , and thus demonstrated the necessity of these cells for memory retrieval.…”

From Engrams to Pathologies of the Brain

“…In recent years, numerous groups have developed novel strategies for visualizing and manipulating defined sets of cells that were either naturally or artificially biased to be active during memory formation or retrieval (Koya et al, 2009; Zhou et al, 2009; Liu et al, 2012; Guenthner et al, 2013; Ramirez et al, 2013, 2015; Cowansage et al, 2014; Denny et al, 2014; Redondo et al, 2014; Tanaka et al, 2014; Yiu et al, 2014; Gore et al, 2015a; Kim et al, 2015; Ryan et al, 2015; Cai et al, 2016; Okuyama et al, 2016; Park et al, 2016; Roy et al, 2016; Stefanelli et al, 2016; Trouche et al, 2016; Ye et al, 2016). After carefully considering the results of these studies, it was recently proposed that at least three conditions must be met for a set of cells to qualify as harboring, or at the very least processing, a component of an engram (Mayford, 2014; Josselyn et al, 2015; Tonegawa et al, 2015).…”

“…For instance, in vivo electrophysiology and histological approaches have revealed sparse activity in DG cells that are exquisitely sensitive to contextual changes (Leutgeb et al, 2007; Satvat et al, 2011). In terms of necessity, lesioning or pharmacologically inactivating the DG often impacts memory encoding but does not have an impact on retrieval (Lee and Kesner, 2004); optogenetically silencing the DG has a similar effect and impairs memory encoding but not retrieval (Kheirbek et al, 2013); yet, chemo- and optogenetically inhibiting ~6%–9% of DG cells that were previously active during learning, but not a similar fraction of randomly active DG cells, impairs memory encoding and retrieval, thus unmasking the real-time necessity of putative engram cells for these stages of memory (Denny et al, 2014; Park et al, 2016). …”

“…For instance, overexpression of the transcription factor CREB can be used to increase neuronal excitability, which permits memories to be allocated, erased, or reactivated both opto- and chemogenetically via a defined set of basolateral amygdala or hippocampus cells (Han et al, 2007, 2009; Zhou et al, 2009; Yiu et al, 2014; Cai et al, 2016; Park et al, 2016; Rashid et al, 2016). A common criticism of these studies, however, is that overexpression of CREB is not natural and there has yet to be a demonstration that these mechanisms exist intrinsically to allocate memories.…”