Antidepressant efficacy in a motivational task and behavioral despair assay are associated with altered limbic pERK1/2, including restored pERK1/2 in the dentate gyrus after stress-related insult.

The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. Here we show that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruit parvalbumin (PV)-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala projecting pyramidal neurons in the IL is dominated by feed-forward inhibition. Selectively silencing PV- but not somatostatin (SOM)-expressing interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impairs extinction recall, whereas silencing IL projectors diminishes fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, these experiments reveal a novel circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.

The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is an immediate early gene that has been widely implicated in hippocampal-dependent learning and memory and is believed to play an integral role in synapse-specific plasticity. Here, we examined the role of Arc/Arg3.1 in amygdala-dependent Pavlovian fear conditioning. We first examined the regulation of Arc/Arg3.

Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and long-term potentiation (LTP) at thalamic and cortical input pathways to the LA. In behavioral experiments, rats given intra-LA infusions of either the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibited dose-dependent impairments or enhancements of fear memory consolidation, respectively. In slice electrophysiology experiments, bath application of Rp-8-Br-PET-cGMPS or the guanylyl cyclase inhibitor LY83583 impaired LTP at thalamic, but not cortical inputs to the LA, while bath application of 8-Br-cGMP or the guanylyl cyclase activator YC-1 resulted in enhanced LTP at thalamic inputs to the LA. Interestingly, YC-1-induced enhancement of LTP in the LA was reversed by concurrent application of the MEK inhibitor U0126, suggesting that the NO-cGMP-PKG signaling pathway may promote synaptic plasticity and fear memory formation in the LA, in part by activating the ERK/MAPK signaling cascade. As a test of this hypothesis, we next showed that rats given intra-LA infusion of the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibit impaired or enhanced activation, respectively, of ERK/MAPK in the LA after fear conditioning. Collectively, our findings suggest that an NO-cGMP-PKG-dependent form of synaptic plasticity at thalamic input synapses to the LA may underlie memory consolidation of Pavlovian fear conditioning, in part, via activation of the ERK/MAPK signaling cascade.Nitric oxide (NO) signaling has been widely implicated in synaptic plasticity and memory formation (Schuman and Madison 1991;Bredt and Snyder 1992;Chapman et al. 1992;Bohme et al. 1993;Zhuo et al. 1994;Bernabeu et al. 1995;Arancio et al. 1996;Doyle et al. 1996;Holscher et al. 1996;Suzuki et al. 1996;Zou et al. 1998;Ko and Kelly 1999;Lu et al. 1999). A highly soluble gas generated by the conversion of L-arginine to L-citrulline by the Ca 2+ -regulated enzyme nitric oxide synthase (NOS), NO is known to have a variety of effects both pre-and postsynaptically. One immediate downstream effector of NO, for example, is soluble guanylyl cyclase (sGC) (Bredt and Snyder 1992;Son et al. 1998;Denninger and Marletta 1999;Arancio et al. 2001). This enzyme directly leads to the formation of cyclic-GMP, and in turn, to the activation of the cGMP-dependent protein kinase (PKG). PKG, in turn, can have a number of effects, including targeting and mobilization of synaptic vesicles in the presynaptic cell, leading to enhanced transmitter release (Hawkins et al. 1993) and also to activation of protein kinase signaling cascades in the postsynaptic cell, leading to activation of transcription and translation that are critical for long-term synaptic plasticity and memory formation (Lu et al. 1999;Chi...

The Neuronal PAS domain protein 4 (Npas4) is a neuronal activity-dependent immediate early gene that has recently been identified as a transcription factor which regulates the transcription of genes that control inhibitory synapse development and synaptic plasticity. The role Npas4 in learning and memory, however, is currently unknown. Here, we systematically examine the role of Npas4 in auditory Pavlovian fear conditioning, an amygdala-dependent form of emotional learning. In our first series of experiments, we show that Npas4 mRNA and protein are regulated in the rat lateral nucleus of the amygdala (LA) in a learning-dependent manner. Further, knockdown of Npas4 protein in the LA via adeno-associated viral (AAV) mediated gene delivery of RNAi was observed to impair fear memory formation, while innate fear and the expression of fear memory were not affected. In our second series of experiments, we show that Npas4 protein is regulated in the LA by retrieval of an auditory fear memory and that knockdown of Npas4 in the LA impairs retention of a reactivated, but not a non-reactivated, fear memory. Collectively, our findings provide the first comprehensive look at the functional role of Npas4 in learning and memory.