Dopamine D₁Receptor Modulates Hippocampal Representation Plasticity to Spatial Novelty

Abstract

The human hippocampus is critical for learning and memory. In rodents, hippocampal pyramidal neurons fire in a location-specific manner, forming relational representations of environmental cues. The importance of glutamatergic systems in learning and in hippocampal neural synaptic plasticity has been shown. However, the role of dopaminergic systems in the response of hippocampal neural plasticity to novel and familiar spatial stimuli remains unclear. To clarify this important issue, we recorded hippocampal neurons from dopamine D 1 receptor knock-out (D1R-KO) mice and their wild-type (WT) littermates under the manipulation of distinct spatial cues in a familiar and a novel environment. Here we report that in WT mice, the majority of place cells quickly responded to the manipulations of distal and proximal cues in both familiar and novel environments. In contrast, the influence of distal cues on spatial firing in D1R-KO mice was abolished. In the D1R-KO mice, the influence of proximal cues was facilitated in a familiar environment, and in a novel environment most of the place cells were less likely to respond to changes of spatial cues. Our results demonstrate that hippocampal neurons in mice can rapidly and flexibly encode information about space from both distal and proximal cues to cipher a novel environment. This ability is necessary for many types of learning, and lacking D1R can radically alter this learning-related neural activity. We propose that D1R is crucially implicated in encoding spatial information in novel environments, and influences the plasticity of hippocampal representations, which is important in spatial learning and memory.

Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

“…The targeting vector was constructed so that the entire coding sequence was deleted by using the following DNA fragments: a 1.2 kb MC1 promoter-diphtheria toxin-A fragment gene (DT-A) for negative selection; the XbaI–XbaI fragment containing the upstream region of the D5R gene; a 2.3 kb PGK promoter- Escherichia coli xanthine-guanine phosphoribosyltransferase gene (gpt); a 1.1 kb MC1 promoter-neomycin gene (neo); a 4.0 kb XbaI–NheI fragment containing the 3′-untranslated region; and a pBluescript plasmid (Figure 1a). This targeting vector was then used to generate D1 dopamine receptor-deficient mice [33].…”

“…The ES cell line used for generation of the D5R-KO mice was previously described [33]. Briefly, CCE ES cells (E14TG2a IV 129-derived ES cells, acquired from Dr. E. Robertson) were cultured as described [34].…”

A behavioral genetics approach to understanding D1 receptor involvement in phasic dopamine signaling

“…The deficits observed by D1R KO in these water-based escape tasks is also observed in dry Barnes maze, in which the animal learns to escape from open field into a tunnel, suggesting that the stress of being in the water is not a key factor (Ortiz et al, 2010). In support of D1 receptor mediation of spatial learning, recording from hippocampal place cells in the CA1 region showed that these cells had difficulty adjusting to changes in distal cues in D1R KO mice, an effect that was exacerbated in a novel environment (Tran et al, 2008). Thus, normal signaling through D1 receptors in the hippocampus appears to be modulate the encoding of spatial information.…”

Ventral tegmental area and substantia nigra neural correlates of spatial learning

“…DA influences these properties, as DA agonists increase place field specificity, and DA antagonists and VTA inactivation decrease place field specificity (Kentros et al 2004;Martig and Mizumori 2010). Further, DA regulates place field stability in context-dependent ways (Gill and Mizumori 2006;Tran et al 2008).…”