Dopamine D1-like receptors in the dorsomedial prefrontal cortex regulate contextual fear conditioning

Stubbendorff, Christine; Hale, Ed; Cassaday, Helen J.; Bast, Tobias; Stevenson, Carl W.

doi:10.1007/s00213-018-5162-7

Cited by 25 publications

(34 citation statements)

References 70 publications

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“…However, the fact that D1-like antagonist infusion during conditioning in other VTA DA targets, i.e. the dorsomedial PFC (Stubbendorff et al 2019), dHPC and BL (Heath et al 2015) reduces contextual fear rather than increasing it, renders difficult to explain our results just by global disinhibition of the DA transmission. Moreover, D1-like antagonism and agonism were both shown to decrease contextual fear when infused in the LHb during conditioning (Chan et al 2017).…”

Section: Discussionmentioning

confidence: 85%

Involvement of the lateral habenula in fear memory

et al. 2020

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Increasing evidence points to the engagement of the lateral habenula (LHb) in the selection of appropriate behavioral responses in aversive situations. However, very few data have been gathered with respect to its role in fear memory formation, especially in learning paradigms in which brain areas involved in cognitive processes like the hippocampus (HPC) and the medial prefrontal cortex (mPFC) are required. A paradigm of this sort is trace fear conditioning, in which an aversive event is preceded by a discrete stimulus, generally a tone, but without the close temporal contiguity allowing for their association based on amygdala-dependent information processing. In a first experiment, we analyzed cellular activations (c-Fos expression) induced by trace fear conditioning in subregions of the habenular complex, HPC, mPFC and amygdala using a factorial analysis to unravel functional networks through correlational analysis of data. This analysis suggested that distinct LHb subregions engaged in different aspects of conditioning, e.g. associative processes and onset of fear responses. In a second experiment, we performed chemogenetic LHb inactivation during the conditioning phase of the trace fear conditioning paradigm and subsequently assessed contextual and tone fear memories. Whereas LHb inactivation did not modify rat's behavior during conditioning, it induced contextual memory deficits and enhanced fear to the tone. These results demonstrate the involvement of the LHb in fear memory. They further suggest that the LHb is engaged in learning about threatening environments through the selection of relevant information predictive of a danger.

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Section: Discussionmentioning

confidence: 85%

Involvement of the lateral habenula in fear memory

et al. 2020

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“…In particular, the D1-like receptor subfamily, which includes the dopamine receptor type 1 (D1R) and D5R, plays a key role in locomotor activity ( Svensson et al, 2017 ) and cognitive and social behaviors ( Cools, 2008 ; Homberg et al, 2016 ). The effects of D1/D5R stimulation by agonists have been thoroughly studied in behavioral tests in rodents ( Zahrt et al, 1997 ; Stubbendorff et al, 2019 ) and primates ( Sawaguchi and Goldman-Rakic, 1991 ; Arnsten et al, 2015 ). Moreover, there is strong evidence that different physiological and pathological states greatly correlate with changes in D1/D5R expression levels.…”

Section: Introductionmentioning

confidence: 99%

Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

McCarthy

Chou-Freed

Rodríguez

et al. 2020

Journal of General Physiology

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Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (CaV2.2) and D1R stimulates CaV2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional CaV2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ∼60% increase in CaV2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in CaV2.2 currents required basally active Gs protein, as well as D1R-CaV2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native CaV currents’ sensitivity to ω-conotoxin-GVIA and their size by ∼49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on CaV2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native CaV currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of CaV2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional CaV2.2 in PFC neurons.

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“…Pantothenate kinase KO mice displayed increases in gene expressions of dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R) in globus pallidus-containing region including striatum [ 44 ]. Interestingly, local infusion of D1R antagonist SCH23390 into AMG, HPC or PFC prior to the fear conditioning impairs fear responses such as freezing [ 45 , 46 ]. Dentate gyrus-specific D1R KO mice showed significant fear memory deficits [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative metabolic profiling of posterior parietal cortex, amygdala, and hippocampus in conditioned fear memory

et al. 2021

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Fear conditioning and retrieval are suitable models to investigate the biological basis of various mental disorders. Hippocampus and amygdala neurons consolidate conditioned stimulus (CS)-dependent fear memory. Posterior parietal cortex is considered important for the CS-dependent conditioning and retrieval of fear memory. Metabolomic screening among functionally related brain areas provides molecular signatures and biomarkers to improve the treatment of psychopathologies. Herein, we analyzed and compared changes of metabolites in the hippocampus, amygdala, and posterior parietal cortex under the fear retrieval condition. Metabolite profiles of posterior parietal cortex and amygdala were similarly changed after fear memory retrieval. While the retrieval of fear memory perturbed various metabolic pathways, most metabolic pathways that overlapped among the three brain regions had high ranks in the enrichment analysis of posterior parietal cortex. In posterior parietal cortex, the most perturbed pathways were pantothenate and CoA biosynthesis, purine metabolism, glutathione metabolism, and NAD+ dependent signaling. Metabolites of posterior parietal cortex including 4′-phosphopantetheine, xanthine, glutathione, ADP-ribose, ADP-ribose 2′-phosphate, and cyclic ADP-ribose were significantly regulated in these metabolic pathways. These results point to the importance of metabolites of posterior parietal cortex in conditioned fear memory retrieval and may provide potential biomarker candidates for traumatic memory-related mental disorders.

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Dopamine D1-like receptors in the dorsomedial prefrontal cortex regulate contextual fear conditioning

Cited by 25 publications

References 70 publications

Involvement of the lateral habenula in fear memory

Involvement of the lateral habenula in fear memory

Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

Comparative metabolic profiling of posterior parietal cortex, amygdala, and hippocampus in conditioned fear memory

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