Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory

Abstract

Activation of the hippocampal dopamine 1-class receptors (D1R and D5R) are implicated in contextual fear conditioning (CFC). However, the specific role of the D1R versus D5R in hippocampal dependent CFC has not been investigated. Generation of D1R-and D5R-specific in situ hybridization probes showed that D1R and D5R mRNA expression was greatest in the dentate gyrus (DG) of the hippocampus. To identify the role of each receptor in CFC we generated spatially restricted KO mice that lack either the D1R or D5R in DG granule cells. DG D1R KOs displayed significant fear memory deficits, whereas DG D5R KOs did not. Furthermore, D1R KOs but not D5R KOs, exhibited generalized fear between two similar but different contexts. In the familiar home cage context, c-Fos expression was relatively low in the DG of control mice, and it increased upon exposure to a novel context. This level of c-Fos expression in the DG did not further increase when a footshock was delivered in the novel context. In DG D1R KOs, DG c-Fos levels in the home cage was higher than that of the control mice, but it did not further increase upon exposure to a novel context and remained at the same level upon a shock delivery. In contrast, the levels of DG c-Fos expression was unaffected by the deletion of DG D5R neither in the home cage nor upon a shock delivery. These results suggest that DG D1Rs, but not D5Rs, contribute to the formation of distinct contextual representations of novel environments. T he hippocampus is crucial for aversive Pavlovian conditioning, such as contextual fear conditioning (CFC) (1, 2). In CFC, the conditioned stimulus (context) is paired with the unconditioned stimulus (footshock), and after pairing, the context serves as a cue to predict a potential footshock (3, 4). Although the role of dopamine has been studied in the context of reward learning (5), evidence suggests that midbrain dopaminergic neurons are also important for aversive Pavlovian conditioning (6-9). In line with this evidence, hippocampal encoding of novel and contextual information is linked to dopamine release via excitation of dopamine neurons of the midbrain (5, 10, 11). Additionally, delivery of aversive stimuli, such as a footshock, results in increased dopaminergic neuron activity (12). Moreover, inactivation of hippocampal D1Rs and D5Rs attenuates contextual fear memory (13). Thus, it follows that delivery of an aversive stimulus activates midbrain dopamine neurons that project to the hippocampus, which is crucial for encoding novel contextual cues (12,14,15). Activation of hippocampal D1Rs and D5Rs may then strengthen the encoding of novel contextual information during CFC.The precise role of subregion-specific D1R or D5R activation in hippocampal-dependent learning and memory is unknown. This is in part due to the inability to discriminate between and spatially restrict D1R from D5R function (16-18), which is an important caveat because each receptor is involved in modulating distinct neuronal processes (19)(20)(21)(22). Indeed, there is a lack of con...

Fear Memory

“…Recent compelling evidence indicates that the DG is also a key structure for CFC, perhaps the main structure involved (304,350,518,556,574). As discussed above, long-standing research has suggested repeatedly that the hippocampus is used mostly for the encoding and early storage of contextual fear and the amygdala is used essentially for modulation (265,(401)(402)(403)(404)545).…”

“…Nowadays hippocampus and amygdala are both viewed as important for the processing of many types of information, and in particular for memory consolidation in the first few hours after acquisition (125,226,265,272,401,403,657). Fear conditioning in particular relies on CS-US interactions in the DG and in the LA (295,328,350,448,574). After all, this fits better with the findings on humans with large bilateral temporal lobe lesions (493,589), specifically those with lesions restricted to the hippocampus (308,549,664,686), who have consistently been shown to have a general incapacity to retain new declarative memories of any kind, but to remember well memories acquired weeks or months before the lesion, and, importantly, do not show appreciable deficits in scene construction (of a picture they see) while consistently losing memory items relevant to that scene (308).…”

“…The neurons themselves are individually stimulated by light in the hope that the stimulation will elicit the behavior under study or its close correlates. This would mean that the selected neuron or neurons actually are part of the engram, but tells little about the molecular mechanisms and nothing about eventual parallel circuits involved (352,518,561,574). In spite of the limitations mentioned above (parallel circuits that may become vicarious, intricacy of molecular systems involved), the optogenetic procedures offer the best hope so far of eventually tracing down the main circuits responsible for a particular memory or memories to the neurons involved in them.…”

“…Thus some DG cells have been identified as carrying (having) the engram for CFC (350,556,574); when these neurons are stimulated by light of the appropriate wavelength, they elicit freezing behavior in the context in which the animals had been trained (the typical CR for CFC). The DG engram cells have a denser dendritic tree, more spines, and a larger excitatory postsynaptic current triggered by entorhinal afferents (350,556).…”

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

“…Although we did not perform direct comparisons between the DH and RSC (because the experiments were performed separately, at different times, and in different behavioral rooms, resulting in different freezing levels in vehicle controls), the observed effects point toward a model of muscarinic contribution to retrieval that is multifaceted and non-uniform across brain regions. Unlike other neurotransmitter receptors such as NMDAR (Gao et al 2010), AMPA receptors (Schiapparelli et al 2006;Bannerman 2009), adrenergic receptors (Gibbs and Summers 2002;Galeotti et al 2004), and dopamine receptors (Sarinana et al 2014;Sarinana and Tonegawa 2016) for which the roles of specific receptor subunits or subtypes are clearly discriminable in various memory processes, it seems that activation of several mAChR subtypes may be necessary to maximally effect one process. This model is consistent with findings using electrophysiological approaches, which demonstrate that cortical M 1 , M 2 , and M 4 together exert a "triad of effects" (M 1 increases neuronal firing rates, M 2 mediates a decrease in cellular inhibition, and M 4 depresses excitatory transmission), which may underlie attention and learning (Gigout et al 2012).…”