Segregated Populations of Hippocampal Principal CA1 Neurons Mediating Conditioning and Extinction of Contextual Fear

Abstract

Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signalregulated kinase (Erk) additionally acts as a central mediator of fear extinction. It is not known however, whether these molecular events take place in overlapping or nonoverlapping neuronal populations. By using mouse models of conditioning and extinction of fear, we set out to determine the time course of cFos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos ϩ and pErk ϩ cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were further used to label in vivo Fos ϩ hippocampal cells during conditioning followed by pErk immunostaining after extinction. The results showed that these signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. These results demonstrate that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum.

HDAC1 Regulates Fear Extinction in Mice

“…Previous data showed that hippocampal c-FOS levels are elevated after exposure to E1 but gradually decrease throughout extinction training (Tronson et al, 2009). In line with these data, we found that in our fear extinction paradigm, hippocampal expression of the c-Fos gene gradually declines throughout extinction training when measured 1 h after exposure to each extinction trial.…”

“…Here, single exposure of rodents to a novel context followed by an electric footshock elicits the acquisition of hippocampus-dependent fear memory that is measured as the amount of aversive freezing behavior. During extinction training, animals are reexposed to the conditioned context on subsequent days without receiving the footshock again (extinction trial, E), which eventually results in the decline of the freezing response (Fischer et al, 2004;Sananbenesi et al, 2007;Fischer and Tsai, 2008;Tronson et al, 2009). Thus, we decided to test whether elevated HDAC1 levels would affect contextual fear extinction.…”

The roles of protein kinases in learning and memory

“…Extinction training of fear LTM induces ERK1/2 phosphorylation in the amygdala and hippocampus (Herry et al 2006;Fischer et al 2007). The time course of ERK1/2 phosphorylation indicates that ERK1/2 are transient, and are in part nuclear in hippocampal CA1 neurons Tronson et al 2009). Such a pattern of activation is consistent with a putative role for ERK1/2 activation in activation of transcription underlying consolidation of extinction memory.…”

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear

“…Impaired ERK Activation in Pyramidal mPFC-IL Neurons of TgNTRK3 Mice ERK activation, which can be triggered by the NT3/TrkC intracellular signaling cascade (Li et al, 2014;Reichardt, 2006), is necessary for successful fear extinction in rodents (Fischer et al, 2007;Tronson et al, 2009). We therefore reasoned that altered NT3/TrkC function might disturb fear extinction memory in TgNTRK3 mice due to impaired ERK signaling.…”

“…Therefore, the NT3 deficit observed in TgNTRK3 animals is likely to result in a deficit in the activation of the NT3/TrkC downstream pathway ERK. Since activation of ERK, as measured by its phosphorylation levels, is associated with successful fear extinction (Fischer et al, 2007;Tronson et al, 2009), reduced ERK phosphorylation in the mPFC-IL of TgNTRK3 in turn may explain the impairment in fear extinction memory observed in the mutant mice. In fact, TgNTRK3 animals showed a reduction in ERK phosphorylation in mPFC-IL excitatory neurons along with a reduction in neuronal activation (as measured by c-Fos levels).…”