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In the CA3 region, the ventral component shows the highest D2R expression. All layers of the ventral CA3 region, namely the Stratum oriens (so) (A), pyramidal cell layer (pcl) (B), Stratum radiatum (sr) (C), and Stratum lacunosum-moleculare (slm) (D) display high D2R levels compared to the dorso-intermediate CA3. Values expressed in arbitrary units (a.u.). Error bars indicate SEM. *p < 0.05, **p < 0.01, ***p < 0.001. so, Stratum oriens; pcl, pyramidal cell layer; sr, Stratum radiatum; and slm, Stratum lacunosum-moleculare.
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Dopamine D2-like receptors (D2R) play an important role in the regulation of hippocampal neuronal excitability and contribute to the regulation of synaptic plasticity, the encoding of hippocampus-dependent memories and the regulation of affective state. In line with this, D2R are targeted in the treatment of psychosis and affective disorders. It ha...
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Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest...
Citations
... In fact, both extracellular dopamine levels 15 and expression of dopamine receptor subtypes show gradual changes along the longitudinal axis of the rat hippocampus. 7,16 Putting all these pieces of information together, the distinct interaction of inhibitory GABAergic iScience Article in IH and VH CA1 PCs compared to the DH (IH: À70.52 G 0.57 mV, and VH: À70.62 G 0.50 mV vs. DH: À75.37 G 0.57 mV; ANOVA F (2,58) = 24.91 p < 0.0001, post hoc Tukey-test p < 0.0001; Figure 1B). Next, we determined AP frequencies induced by somatically injected step currents ( Figures 1C and 1D). ...
Synaptic plasticity in the hippocampus underlies episodic memory formation, with dorsal hippocampus being instrumental for spatial memory whereas ventral hippocampus is crucial for emotional learning.
Here, we studied how GABAergic inhibition regulates physiologi-cally relevant low repeat spike timing-dependent LTP (t-LTP) at Schaffer collateral-CA1 synapses along the dorsoventral hippo-campal axis. We used two t-LTP protocols relying on only 6 repeats of paired spike-firing in pre- and postsynaptic cells within 10 s that differ in postsynaptic firing patterns. GABA-A receptor mechanisms played a greater role in blocking 6x 1:1 t-LTP that recruits single postsynaptic action potentials. 6x 1:4 t-LTP that depends on postsynaptic burst-firing unexpectedly required intact GABA-B receptor signaling. The magnitude of both t-LTP-forms decreased along the dorsoventral axis, despite increasing excitability and basal synaptic strength in this direction. This suggests that GABAergic inhibition contributes to the distinct roles of dorsal and ventral hippocampus in memory formation.
... Dopamine D2-like receptors (D2R) have been shown to influence synaptic plasticity and hippocampal function, including learning and memory [33,34]. D2 receptor expression in the hippocampus correlates with memory performance in adult males [35], and high levels of D2 receptor mRNA have been identified in the hippocampal dentate gyrus [36]. ...
... D2 receptor expression in the hippocampus correlates with memory performance in adult males [35], and high levels of D2 receptor mRNA have been identified in the hippocampal dentate gyrus [36]. Numerous other studies identify hippocampal D2 expression in humans and rodents [18,33,37,38]. However, the full expression profile of D2 receptors in the hippocampus, including after TBI, has not been elucidated. ...
... Fewer D2-expressing neurons were also observed in the hilus and in the CA1 stratum radiatum of female sham mice. These findings are consistent with previous descriptive studies that examined D2 receptor expression patterns in the hippocampus of male and female mice [18], and in male mice [33,38]. Several novel advances are conferred by the current work using a genetic model combined with high-resolution through-focus confocal microscopy. ...
Traumatic brain injury (TBI) is a major health concern. Each year, over 50 million individuals worldwide suffer from TBI, and this leads to a number of acute and chronic health issues. These include affective and cognitive impairment, as well as an increased risk of alcohol and drug use. The dopaminergic system, a key component of reward circuitry, has been linked to alcohol and other substance use disorders, and previous research indicates that TBI can induce plasticity within this system. Understanding how TBI modifies the dopaminergic system may offer insights into the heightened substance use and reward-seeking behavior following TBI. The hippocampus, a critical component of the reward circuit, is responsible for encoding and integrating the spatial and salient aspects of rewarding stimuli. This study explored TBI-related changes in neuronal D2 receptor expression within the hippocampus, examining the hypothesis that sex differences exist in both baseline hippocampal D2 receptor expression and its response to TBI. Utilizing D2-expressing tdTomato transgenic male and female mice, we implemented either a sham injury or the lateral fluid percussion injury (FPI) model of TBI and subsequently performed a region-specific quantification of D2 expression in the hippocampus. The results show that male mice exhibit higher baseline hippocampal D2 expression compared to female mice. Additionally, there was a significant interaction effect between sex and injury on the expression of D2 in the hippocampus, particularly in regions of the dentate gyrus. Furthermore, TBI led to significant reductions in hippocampal D2 expression in male mice, while female mice remained mostly unaffected. These results suggest that hippocampal D2 expression varies between male and female mice, with the female dopaminergic system demonstrating less susceptibility to TBI-induced plasticity.
... Negative control tests, where the receptor antibodies were omitted from the protocols described above, were performed to exclude confounds (not shown). The effectiveness of the D1R and D2R antibodies used here was previously confirmed using Western blotting (Dubovyk and Manahan-Vaughan 2019;Zou et al. 2005). ...
... For the optical density analysis of DA receptor expression, we used a similar approach as before (Dubovyk and Manahan-Vaughan 2019). In brief, we initially selected the slices of interest by means of light microscope inspection and subsequently scanned them with a high-precision slide scanner (Axio Scan.Z1, Zeiss, Jena, Germany). ...
The dopaminergic (DA) system regulates both motor function, and learning and memory. The cerebellum supports motor control and the acquisition of procedural memories, including goal-directed behavior, and is subjected to DA control. Its fastigial nucleus (FN) controls and interprets body motion through space. The expression of dopamine receptors has been reported in the deep cerebellar nuclei of mice. However, the presence of dopamine D1-like (D1R) and D2-like (D2R) receptors in the rat FN has not yet been verified. In this study, we first confirmed that DA receptors are expressed in the FN of adult rats and then targeted these receptors to explore to what extent the FN modulates goal-directed behavior. Immunohistochemical assessment revealed expression of both D1R and D2R receptors in the FN, whereby the medial lateral FN exhibited higher receptor expression compared to the other FN subfields. Bilateral treatment of the FN with a D1R antagonist, prior to a goal-directed pellet-reaching task, significantly impaired task acquisition and decreased task engagement. D2R antagonism only reduced late performance post-acquisition. Once task acquisition had occurred, D1R antagonism had no effect on successful reaching, although it significantly decreased reaching speed, task engagement, and promoted errors. Motor coordination and ambulation were, however, unaffected as neither D1R nor D2R antagonism altered rotarod latencies or distance and velocity in an open field. Taken together, these results not only reveal a novel role for the FN in goal-directed skilled reaching, but also show that D1R expressed in FN regulate this process by modulating motivation for action.
... Dopamine (DA) is considered one of the most important modulators of hippocampus-dependent neurocognitive function (Edelmann & Lessmann, 2018;El-Ghundi et al., 2007). Animal models suggest heterogeneous innervation patterns by distinct DA sources (Gasbarri et al., 1994;Ishikawa et al., 1982;Kempadoo et al., 2016;Verney et al., 1985), as well as spatial variation in hippocampal postsynaptic DA receptors (Dubovyk & Manahan-Vaughan, 2019), across both transverse and longitudinal hippocampal axes, likely allowing for separation between DA modulation of distinct hippocampus-dependent behaviors (Edelmann & Lessmann, 2018). Relatedly, the human hippocampus has been suggested as part of distinct DA circuits on the basis of anteroposterior variation in its functional connectivity with midbrain and striatal regions (Kahn & Shohamy, 2013;Nordin et al., 2021;Nyberg et al., 2016). ...
The hippocampus is a complex structure critically involved in numerous behavior-regulating systems. A multidimensional account of the hippocampus functional integration with neocortex, however, remains to be established and evaluated in terms of functional specialization and cognitive decline in aging. Here, we identify two long-axis modes of cortical functional connectivity (FC) during rest: a principal gradient of gradual anterior-posterior variation reflecting a task-positive/task-negative cortical motif, and a second-order gradient, representing unimodal-transmodal macroscale cortical organization. The second-order gradient predicted episodic memory and reflected underlying distribution of postsynaptic dopamine D1 receptors, suggesting shared principles of functional and neuromolecular organization. Older age was associated with less distinct transitions in FC along gradients, and a youth-like gradient profile, i.e. maintained distinctiveness, was linked to superior memory, highlighting age-related gradient dedifferentiation as a potential marker of cognitive decline. Our results support the notion that hippocampal function stands to inform general principles of brain organization, and emphasize a critical role of a second-order long-axis connectivity mode in mnemonic function across the lifespan.
... Local inhibition of D1 and D2 receptors in the intermediate CA1 was also shown to cause an impairment in the acquisition and reinstatement of morphine-induced conditioned place preference (Assar et al., 2016). These results are in agreement with studies that examined the distribution of D1 and D2 receptors in the hippocampus (Gangarossa et al., 2012;Puighermanal et al., 2015Puighermanal et al., , 2017 demonstrating an increasing gradient of expression of D2 receptors along the dorso-ventral axis (Dubovyk and Manahan-Vaughan, 2019). ...
The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus. Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.
... Dopamine D2 receptors (D 2 R) in the amygdala are vital in regulating aversive fear memories and anxiety processing [16][17][18]. Stressful events may negatively regulate the dopaminergic system and induce anxiety or depressionlike behaviors [19,20]. Our previous results revealed that restraint stress increased the dopaminergic neurotransmission in the amygdala and induced depression-like behavior (decreased sucrose preference) [21]. ...
Background
The present study assessed the influence of recurrent social isolation stress on the aversive memory extinction and dopamine D 2 receptors (D 2 R) expression in the amygdala and the hippocampus subnuclei. We also analyzed the expression of epigenetic factors potentially associated with fear extinction: miRNA-128 and miRNA-142 in the amygdala.
Methods
Male adult fear-conditioned rats had three episodes of 48 h social isolation stress before each fear extinction session in weeks intervals. Ninety minutes after the last extinction session, the D 2 R expression in the nuclei of the amygdala and the hippocampus (immunocytochemical technique), and mRNA levels for D 2 R in the amygdala were assessed (PCR). Moreover, we evaluated the levels of miRNA-128 and miRNA-142 in the amygdala.
Results
It was found that recurrent social isolation stress decreased the fear extinction rate. The extinguished isolated rats were characterized by higher expression of D 2 R in the CA1 area of the hippocampus compared to the extinguished and the control rats. In turn, the isolated group presented higher D 2 R immunoreactivity in the CA1 area compared to the extinguished, the control, and the extinguished isolated animals. Moreover, the extinguished animals had higher expression of D 2 R in the central amygdala than the control and the extinguished isolated rats. These changes were accompanied by the increase in miRNA-128 level in the amygdala in the extinguished isolated rats compared to the control, the extinguished, and the isolated rats. Moreover, the extinguished rats had lower expression of miRNA-128 compared to the control and the isolated animals.
Conclusions
Our results suggest that social isolation stress impairs aversive memory extinction and coexists with changes in the D 2 R expression in the amygdala and hippocampus and increased expression of miRNA-128 in the amygdala.
... In contrast, Smiałowski postulated that high concentrations of D2R agonists cause spontaneous firing of CA1 pyramidal neurons [7]. Other studies have also shown that the dorsal hippocampus (dH) is involved in the processing of emotional information [8]. ...
... The involvement of D2R signaling in modulating hippocampal synaptic flexibility has also been described by others [8]. Functionally, in various studies, D2R is involved in hippocampal-dependent learning and memory, so the systemic use of receptor blockade creates a set of learning and memory deficits [9]. ...
Background: As previous studies show, several effects of morphine are induced by the dopaminergic system. Sulpiride is a dopamine D2 receptor (DAD2) antagonist widely used in clinics to treat DArelated disorders. DAD2 receptors are abundant at hippocampal cornu ammonis (CA1). Objectives: This study aimed to investigate the possible interaction of morphine and sulpiride on DA synapses in CA1. Materials & Methods: In this study, 48 Wistar rats weighing 220 to 250 g were used. These animals were classified into eight groups (6 rats per group): saline control group (1 mL/kg), morphine group (5 mg/kg), sulpiride groups alone (1, 2, and 4 mg/kg) and sulpiride groups (1, 2, and 4 mg/ kg)+morphine (5 mg/kg). Saline or substances were injected once intraperitoneally. After 48 h, the animals’ brains were removed under anesthesia and placed in 10% formalin for fixation. Then, 3- to 4-μm slices were cut from these tissues, and the DA synapse was examined by histochemistry and immunohistochemistry techniques. The data were statistically analyzed by the analysis of variance. Results: The control group had DA synapses and healthy neurons. A relative increase in DA synapses compared to the control group was observed in the morphine and single sulpiride groups. However, in sulpiride+morphine groups, DA synapses were reduced compared to morphine or sulpiride alone, but neurons were not destroyed. Conclusion: The interaction effect of sulpiride and morphine in the CA1 region may decrease DA synapses.
... They exhibit differential rates of neurogenesis and each displays a distinct pattern of neurotransmitter receptor distribution [155][156][157]. In addition, the septal/temporal divisions of the hippocampus exhibit significant differences in behavior-induced arc gene expression [158], distinct transcriptional and epigenetic effects in response to an enriched environment or physical activity [82,159], and distinct pathological responses throughout aging [160]. The dorsal hippocampus is associated with spatial memory and contextual information processing, while the ventral hippocampus is related to emotional behavior in association with fear, anxiety, and reward processing [161][162][163]. ...
As aging and cognitive decline progresses, the impact of a sedentary lifestyle on the appearance of environment-dependent cellular morphologies in the brain becomes more apparent. Sedentary living is also associated with poor oral health, which is known to correlate with the rate of cognitive decline. Here, we will review the evidence for the interplay between mastication and environmental enrichment and assess the impact of each on the structure of the brain. In previous studies, we explored the relationship between behavior and the morphological features of dentate gyrus glial fibrillary acidic protein (GFAP)-positive astrocytes during aging in contrasting environments and in the context of induced masticatory dysfunction. Hierarchical cluster and discriminant analysis of GFAP-positive astrocytes from the dentate gyrus molecular layer revealed that the proportion of AST1 (astrocyte arbors with greater complexity phenotype) and AST2 (lower complexity) are differentially affected by environment, aging and masticatory dysfunction, but the relationship is not straightforward. Here we re-evaluated our previous reconstructions by comparing dorsal and ventral astrocyte morphologies in the dentate gyrus, and we found that morphological complexity was the variable that contributed most to cluster formation across the experimental groups. In general, reducing masticatory activity increases astrocyte morphological complexity, and the effect is most marked in the ventral dentate gyrus, whereas the effect of environment was more marked in the dorsal dentate gyrus. All morphotypes retained their basic structural organization in intact tissue, suggesting that they are subtypes with a non-proliferative astrocyte profile. In summary, the increased complexity of astrocytes in situations where neuronal loss and behavioral deficits are present is counterintuitive, but highlights the need to better understand the role of the astrocyte in these conditions.
... Whole slide images were acquired with a digital camera (QIC-F-CLR-12, QImaging, Surrey, Canada), using the virtual tissue 2D module of Neurolucida. Immunohistochemical background staining was corrected by subtracting density values obtained in the corpus callosum to minimize inter-array differences 59 . Luminance information ranging from 0 to 255 was determined for the whole area 8 . ...
In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex and hippocampus occurs. Two fundamental characteristics comprise widespread changes in the relative expression of GABA and glutamate receptors and debilitation of hippocampal synaptic plasticity. Here, we explored whether recovery from adaptive changes in the expression of plasticity-related neurotransmitter receptors and hippocampal synaptic plasticity occurs in the time-period of up to 12 months after onset of sensory loss. We compared receptor expression in CBA/J mice that develop hereditary blindness, with CBA/CaOlaHsd mice that have intact vision and no deficits in other sensory modalities throughout adulthood. GluN1-subunit expression was reduced and the GluN2A:GluN2B ratio was persistently altered in cortex and hippocampus. GABA-receptor expression was decreased and metabotropic glutamate receptor expression was altered. Hippocampal synaptic plasticity was persistently compromised in vivo. But although LTP in blind mice was chronically impaired throughout adulthood, a recovery of the early phase of LTP became apparent when the animals reached 12 months of age. These data show that cortical and hippocampal adaptation to early postnatal blindness progresses into advanced adulthood and is a process that compromises hippocampal function. A partial recovery of hippocampal synaptic plasticity emerges in advanced adulthood, however.
... The DRD2 gene is located on chromosome 11q23.2. It encodes two molecularly distinct isoforms [the D2 long (D2L) and the D2 short (D2S)] with distinct functions (Gluskin and Mickey 2016;Dubovyk and Manahan-Vaughan 2019). Zhang et al. characterized two SNPs within DRD2, one in intron 5 rs2283265 and the second in intron 6 rs1076560. ...
This study aimed to investigate the association between selected variants of genes related to dopamine metabolism pathways and the risk of and progression of Parkinson’s disease (PD). This prospective cohort study was conducted in one academic teaching hospital. The study was conducted on 126 patients diagnosed with idiopathic Parkinson’s disease. Blood samples were collected to conduct a genotyping of MAOB, DRD1, DRD2, and DDC genes. Genotype and allele frequencies of MAOB (rs1799836) variants were not associated with the course of PD. Genotype and allele frequencies of DRD2 (rs2283265) variants were associated with risk of dementia ( p = 0.001) and resulted in parts II and III of the UPDRS scale ( p = 0.001). Genotype and allele frequencies of DRD2 (rs1076560) variants were associated with risk of dementia ( p = 0.001) and resulted in parts II and III of the UPDRS scale ( p = 0.001). Genotype and allele frequencies of DDC (rs921451) variants were not associated with the course of PD.
