Norepinephrine and ß1-adrenergic signaling facilitate activation of hippocampal CA1 pyramidal neurons during contextual memory retrieval

Abstract

We previously described a role for adrenergic signaling in the hippocampus to promote contextual and spatial memory retrieval. A subsequent study performing expression analysis of the immediate-early gene (IEG) Arc suggested that activation of CA1 but not CA3 pyramidal neurons during memory retrieval is impaired in the absence of NE. The current study sought to confirm and extend those observations by performing expression analysis of a second IEG product, Fos, following a much greater variety of testing conditions. In mutant mice lacking NE, induction of Fos was normal in all regions of the hippocampus and amygdala shortly after fear conditioning. In contrast, when testing contextual fear one day after training, induction of Fos in CA1 and the central nucleus of the amygdala (CeA), but not CA3, the dentate gyrus or other amygdaloid nuclei, was impaired in the mutant mice. This pattern corresponded to the memory retrieval deficit exhibited by these mice. On the other hand, induction was normal in CA1 and CeA when testing cued fear one day after training, or contextual fear one week or one month after training, conditions in which retrieval is normal in the absence of NE. Acute restoration of NE in the mutant mice before testing but not before training rescued retrieval of contextual fear and restored Fos induction in CA1 and CeA. Because NE facilitates retrieval through the activation of β1-adrenergic receptors, β1 knockout mice were also examined and found to exhibit reduced induction of Fos in CA1 and CeA following retrieval. Based on these and previous results, we hypothesize that adrenergic signaling is critical for the full activation of CA1 pyramidal neurons in response to excitatory input from CA3 pyramidal neurons conveying retrieved contextual information.

Impairment of Catecholamine Systems during Induction of Long-Term Potentiation at Hippocampal CA1 Synapses in HPC-1/Syntaxin 1A Knock-out Mice

“…3B), because decreased catecholamine levels during LTP induction increase the stimulus strength required for LTP. This expectation is supported by studies that show adrenergic signaling in the hippocampus is critical for the retrieval of contextual and spatial memories (Murchison et al, 2004(Murchison et al, , 2011. To clarify the relationship between impaired synaptic plasticity and behavioral abnormalities in STX1A Ϫ/Ϫ mice, additional behavioral analyses are needed.…”

The Role of Norepinephrine in Amygdala Dependent Fear Learning and Memory

“…Furthermore, anisomycin attenuated c-Fos (cellular FBJ osteosarcoma oncogene) immunoreactivity (assessed by application of foot-shocks) by inhibiting the protein synthesis in BLA, and thereby providing some possible challenges for required de novo synthesis for long-term memory generation. The activity of c-Fos within several major nuclei of amygdala was up to 10 fold higher after 2 h of contextual fear training (Murchison et al, 2011). This increase was independent of the presence of ligand for adrenergic receptors (NE and E) as in the case of previously established Dbh -/-mice (see Murchison et al, 2011).…”

“…The activity of c-Fos within several major nuclei of amygdala was up to 10 fold higher after 2 h of contextual fear training (Murchison et al, 2011). This increase was independent of the presence of ligand for adrenergic receptors (NE and E) as in the case of previously established Dbh -/-mice (see Murchison et al, 2011). Under these conditions, the lowest level of c-Fos was in the CeA.…”

Elements toward novel therapeutic targeting of the adrenergic system

“…Moreover, a2-ARs appear to play a role in emotional memory (de Quervain et al, 2007). Importantly, within the amygdala and hippocampus, β-ARs have been linked to memory function processes (Bush et al, 2010;Gibbs and Summers, 2005;Murchison et al, 2011). Indeed, β-ARs are implicated in emotional memory (Cahill et al, 1996) and learning process (Roullet and Sara, 1998;Rutecki, 1995;Sternberg et al, 1985).…”