CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala

Abstract

The mechanisms that determine how information is allocated to specific regions and cells in the brain are fundamentally important for memory capacity, storage and retrieval, but are poorly understood. Here, we manipulated CREB in a subset of lateral amygdala (LA) neurons with a modified Herpes Simplex Virus (HSV), and reversibly inactivated transfected neurons with the Drosophila allatostatin G-protein-coupled receptor (AlstR)/ligand system. We found that inactivation of the HSV-CREB subpopulation of neurons with allatostatin (AL) during training disrupted memory for tone conditioning, while inactivation of a similar proportion of HSV-LacZ control neurons did not. Whole-cell recordings of fluorescently tagged HSV-CREB neurons revealed that neurons with higher CREB levels are more excitable than neighboring neurons, and show larger synaptic efficacy changes following conditioning. Our findings demonstrate that CREB modulates the allocation of fear memory to specific cells in lateral amygdala, and suggest that neuronal excitability plays a key role in this process.

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

“…Extensive studies have shown that CREB is not only a requirement but also a critical driving force for the consolidation of long‐term conditioned fear memories (Bourtchuladze et al ., 1994; Kida et al ., 2002; Viosca et al ., 2009; Zhou et al ., 2009). We investigated whether decreased PKA‐CREB signaling induced by decreased O‐GlcNAcylation affects auditory fear conditioning in mice.…”

Neuronal Allocation to a Hippocampal Engram

“…We (Han et al, 2007(Han et al, , 2009Yiu et al, 2014) and others (Zhou et al, 2009;Gouty-Colomer et al, 2016), previously examined how neurons in the lateral nucleus of the amygdala (LA) are allocated to an engram supporting a discrete cue fear memory (in which an initially motivationally neutral auditory cue is paired with an aversive foot shock) (Davis, 1992;LeDoux, 2000;Maren, 2003). Increasing the function of the transcription factor CREB (Ca 2+ /cAMP response element-binding protein) in individual principal LA neurons increased the likelihood that a particular neuron would become part of a fear/threat memory engram (Han et al, 2007(Han et al, , 2009Zhou et al, 2009). Furthermore, genetic ablation or suppression of LA neurons overexpressing CREB (and not an equal number of random LA neurons) impaired memory expression (Han et al, 2009;Zhou et al, 2009).…”

“…Research focusing on other brain regions show that a neuron's participation in a given engram may be biased experimentally by manipulating its intrinsic excitability (Han et al, 2009;Zhou et al, 2009;Sano et al, 2014;Yiu et al, 2014). However, it is unknown whether the same rules of allocation apply to the DG.…”

“…Increasing the function of the transcription factor CREB (Ca 2+ /cAMP response element-binding protein) in individual principal LA neurons increased the likelihood that a particular neuron would become part of a fear/threat memory engram (Han et al, 2007(Han et al, , 2009Zhou et al, 2009). Furthermore, genetic ablation or suppression of LA neurons overexpressing CREB (and not an equal number of random LA neurons) impaired memory expression (Han et al, 2009;Zhou et al, 2009). Subsequent experiments showed that neurons with high CREB function were preferentially allocated to the LA fear memory engram owing to increased excitability (Zhou et al, 2009;Yiu et al, 2014).…”

“…Furthermore, genetic ablation or suppression of LA neurons overexpressing CREB (and not an equal number of random LA neurons) impaired memory expression (Han et al, 2009;Zhou et al, 2009). Subsequent experiments showed that neurons with high CREB function were preferentially allocated to the LA fear memory engram owing to increased excitability (Zhou et al, 2009;Yiu et al, 2014). Specifically, increasing the excitability of a small population of LA neurons in the minutes before training using chemogenetics or optogenetics also resulted in preferential allocation of these more excitable neurons to the resulting engram (Yiu et al, 2014).…”