Dorsal hippocampus and classical fear conditioning to tone and context in rats: Effects of local NMDA‐receptor blockade and stimulation

Abstract

ABSTRACT:Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25 g/side) or of NMDA (0.7 g/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes.

Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

“…Our findings that the pHPC is selectively involved in processing information about environmental cues for which there is a personal history of smoking are consistent with animal studies, in which inactivation of the analogous dorsal HPC has been shown to disrupt expression of psychostimulant CPP (Meyers et al, 2003(Meyers et al, , 2006 and CIR (Fuchs et al, 2005). These animal studies of learned reward are also consistent with human and animal fear conditioning studies, in which the dorsal HPC has been shown to have a central role in context effects (Alvarez et al, 2008;Bast et al, 2003;Maren et al, 2013;Marschner et al, 2008). Interestingly and in contrast with pHPC, aHPC exhibited greater signal in response to smoking, relative to nonsmoking, cues regardless of cue category.…”

Extracellular Hippocampal Acetylcholine Level Controls Amygdala Function and Promotes Adaptive Conditioned Emotional Response

“…* indicates conditioning effect (CS-US pairing vs unpairing); # indicates pharmacological effect (SAL vs SCOP or SAL vs PHY) ditioning to the tone explicitly paired with shock). Previous data have shown that interfering with hippocampal processes can disrupt elemental conditioning (Bast et al, 2003). Here, we show that augmenting the hippocampal cholinergic signal not only disrupts tone fear conditioning but also promotes contextual conditioning.…”

Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice

“…For instance, contextual fear conditioning may depend more on the dorsal hippocampus than the ventral hippocampus [3,54,67]. In support, Lee and Kesner [49] demonstrated that all three subregions of the dorsal hippocampus (CA3, CA1, and dentate gyrus) contribute to the acquisition of contextual memory.…”

“…Although fear conditioning and PPI both depend upon the hippocampus [3,36,49,54,67,85], each task may differentially recruit subregions of the hippocampus [3,36,43,49,54,67,85]. For instance, contextual fear conditioning may depend more on the dorsal hippocampus than the ventral hippocampus [3,54,67].…”

“…Like fear conditioning, PPI is dependent on the hippocampus [3,36,49,54,67,85] and thus may serve as a control for general deficits in hippocampal function during nicotine withdrawal. PPI is a phenomenon in which a low threshold initial stimulus, called a pre-pulse, suppresses subsequent responding to a startling stimulus [40] and is used as a measure of sensory gating [2,23,79].…”