Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex

Interactions between dopamine and N-methyl-D-aspartate receptors (NMDARs) in prefrontal cortex (PFC) and other brain regions are believed to play an important role in normal mental function and neuropsychiatric disorders. In this study, we examined the regulation of NMDAR currents by the dopamine D1 receptor in PFC pyramidal neurons. Application of the D1 receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons. The D1 effect on NMDARs was independent of protein kinase A or protein phosphatase 1, but was abolished by incubation of neurons in Ca2+-free medium. Intracellular application of the Ca2+ chelator, calmodulin, or calmodulin inhibitors largely prevented the D1 modulation of NMDAR currents. Moreover, inhibiting PKC activity or disrupting PKC association with its anchoring protein also significantly reduced the D1 effect on NMDAR currents. This upregulation of NMDAR activity by dopamine D1 receptors and the previous finding on up-regulation of dopamine D1 receptors by NMDAR activation provide a cellular mechanism for the reciprocal interactions between D1 and NMDARs. These interactions may play an important role in modulating synaptic plasticity and thus in cognitive and emotional processes.     

D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex

Dopamine release associated with motivational arousal is thought to drive goal-directed learning and consolidation of acquired memories. This dopamine hypothesis of learning and motivation directly suggests that dopamine is necessary for modifications of excitatory synapses in dopamine terminal fields, including the prefrontal cortex (PFC), to “stamp in” posttrial memory traces. It is unknown how such enabling occurs in native circuits tightly controlled by GABAergic inhibitory tone. Here we report that dopamine, via both D1-class receptors (D1Rs) and D2-class receptors (D2Rs), enables the induction of spike timing–dependent long-term potentiation (t-LTP) in layer V PFC pyramidal neurons over a “window” of more than 30 ms that is otherwise closed under intact inhibitory constraint. Dopamine acts at D2Rs in local GABAergic interneurons to suppress inhibitory transmission, gating the induction of t-LTP. Moreover, dopamine activates postsynaptic D1Rs in excitatory synapses to allow t-LTP induction at a substantially extended, normally ineffective, timing interval (+30 ms), thus increasing the associability of prepost coincident stimuli. Although the D2R-mediated disinhibition alone is sufficient to gate t-LTP at a normal timing (+10 ms), t-LTP at +30 ms requires concurrent activation of both D1Rs and D2Rs. Our results illustrate a previously unrecognized circuit-level mechanism by which dopamine receptors in separate microcircuits cooperate to drive Hebbian synaptic plasticity across a significant temporal window under intact inhibition. This mechanism should be important in functioning of interconnected PFC microcircuits, in which D1Rs and D2Rs are not colocalized but their coactivation is necessary.     

D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex

Two distinct defects are thought to be important for the pathophysiology of schizophrenia. One is an increase of D2 receptors (D2Rs) in the striatum and another is a decrease in the GABAergic function in the prefrontal cortex (PFC). Whether these two defects are functionally linked is not known. We previously reported that selective overexpression of D2Rs in the striatum of the mouse causes behavioral abnormality associated with PFC functions. Using patch-clamp recording, we find that overexpression of D2Rs in the striatum affects inhibitory transmission in the PFC and dopamine (DA) sensitivity. The overexpression of D2Rs in the striatum caused an increase in frequency of spontaneous excitatory postsynaptic currents (EPSCs) in layer V pyramidal neurons, whereas their neuronal excitability was unaffected. In contrast, both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) were significantly decreased in these mice, indicating a reduced inhibitory transmission. Furthermore, in D2R transgenic mice the dopaminergic modulation of evoked IPSCs was shifted, with reduced sensitivity. The change in dopamine sensitivity in the PFC of D2R transgenic mice appears specific for D2Rs because in D2R transgenic mice the effects of D2 agonist but not D1 agonist, on both evoked IPSCs and EPSCs, were reduced. Together, these results indicate that overexpression of D2Rs in the striatum leads to a functional deficit in the GABAergic system. These results provide a functional link between D2R overexpression and GABAergic inhibition in the PFC and suggest that the postulated deficit in GABAergic function in schizophrenia could be secondary to alterations in the striatal dopamine system.     

Changes in dopamine D(2)-receptor modulation of the hypoxic ventilatory response with chronic hypoxia

Modulation of the hypoxic ventilatory response (HVR) by dopamine D(2)-receptors (D(2)-R) in the carotid body (CB) and central nervous system (CNS) are hypothesized to contribute to ventilatory acclimatization to hypoxia. We tested this with blockade of D(2)-R in the CB or CNS in conscious rats after 0, 2 and 8 days of hypoxia. On day 0, CB D(2)-R blockade significantly increased VI and frequency (fR) in hyperoxia (FI(O(2))=0.30), but not hypoxia (FI(O(2))=0.10). CNS D(2)-R blockade significantly decreased fR in hypoxia only. On day 2, neither CB nor CNS D(2)-R blockade affected VI or fR. On day 8, CB D(2)-R blockade significantly increased hypoxic VI and fR. CNS D(2)-R blockade significantly decreased hypoxic VI and fR. CB and CNS D(2)-R modulation of the HVR decreased after 2 days of hypoxia, but reappeared after 8 days. Changes in the opposing effects of CB and CNS D(2)-R on the HVR during chronic hypoxia cannot completely explain ventilatory acclimatization in rats.     

Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function

Enhanced dopamine efflux in the prefrontal cortex is a well-documented response to acute stress. However, the underlying mechanism(s) for this response is unknown. Using in vivo microdialysis, we demonstrate that blocking glucocorticoid receptors locally within the rat prefrontal cortex results in a reduction in stress-evoked dopamine efflux. In contrast, blocking glucocorticoid receptors in the ventral tegmental area did not affect stress-evoked dopamine efflux in the prefrontal cortex. Additionally, local administration of corticosterone into the prefrontal cortex increased prefrontal dopamine efflux. The functional impact of enhanced dopamine efflux evoked by acute stress was demonstrated using a cognitive task dependent on the prefrontal cortex and sensitive to impairment in working memory. Notably, stress-induced impairments in cognition were attenuated by blockade of glucocorticoid receptors in the prefrontal cortex. Taken together, these data demonstrate that glucocorticoids act locally within the prefrontal cortex to modulate mesocortical dopamine efflux leading to the cognitive impairments observed during acute stress.     

Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.     

Rapid metabolic evolution in human prefrontal cortex

Human evolution is characterized by the rapid expansion of brain size and drastic increase in cognitive capabilities. It has long been suggested that these changes were accompanied by modifications of brain metabolism. Indeed, human-specific changes on gene expression or amino acid sequence were reported for a number of metabolic genes, but actual metabolite measurements in humans and apes have remained scarce. Here, we investigate concentrations of more than 100 metabolites in the prefrontal and cerebellar cortex in 49 humans, 11 chimpanzees, and 45 rhesus macaques of different ages using gas chromatography-mass spectrometry (GC-MS). We show that the brain metabolome undergoes substantial changes, both ontogenetically and evolutionarily: 88% of detected metabolites show significant concentration changes with age, whereas 77% of these metabolic changes differ significantly among species. Although overall metabolic divergence reflects phylogenetic relationships among species, we found a fourfold acceleration of metabolic changes in prefrontal cortex compared with cerebellum in the human lineage. These human-specific metabolic changes are paralleled by changes in expression patterns of the corresponding enzymes, and affect pathways involved in synaptic transmission, memory, and learning.     

Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons

Dopamine acts mainly through the D1/D5 receptor in the prefrontal cortex (PFC) to modulate neural activity and behaviors associated with working memory. To understand the mechanism of this effect, we examined the modulation of excitatory synaptic inputs onto layer V PFC pyramidal neurons by D1/D5 receptor stimulation. D1/D5 agonists increased the size of N-methyl-d-aspartate (NMDA) component of excitatory postsynaptic currents (EPSCs) through a postsynaptic mechanism. In contrast, D1/D5 agonists caused a slight reduction in the size of the non-NMDA component of EPSCs through a small decrease in release probability. With 20 Hz synaptic trains, we found that the D1/D5 agonists increased depolarization of summating the NMDA component of excitatory postsynaptic potential (EPSP). By increasing the NMDA component of EPSCs, yet slightly reducing release, D1/D5 receptor activation selectively enhanced sustained synaptic inputs and equalized the sizes of EPSPs in a 20-Hz train.     

Risk-dependent reward value signal in human prefrontal cortex

When making choices under uncertainty, people usually consider both the expected value and risk of each option, and choose the one with the higher utility. Expected value increases the expected utility of an option for all individuals. Risk increases the utility of an option for risk-seeking individuals, but decreases it for risk averse individuals. In 2 separate experiments, one involving imperative (no-choice), the other choice situations, we investigated how predicted risk and expected value aggregate into a common reward signal in the human brain. Blood oxygen level dependent responses in lateral regions of the prefrontal cortex increased monotonically with increasing reward value in the absence of risk in both experiments. Risk enhanced these responses in risk-seeking participants, but reduced them in risk-averse participants. The aggregate value and risk responses in lateral prefrontal cortex contrasted with pure value signals independent of risk in the striatum. These results demonstrate an aggregate risk and value signal in the prefrontal cortex that would be compatible with basic assumptions underlying the mean-variance approach to utility.     

The role of prefrontal cortex and posterior parietal cortex in task switching

Human ability to switch from one cognitive task to another involves both endogenous preparation without an external stimulus and exogenous adjustment in response to the external stimulus. In an event-related functional MRI study, participants performed pairs of two tasks that are either the same (task repetition) or different (task switch) from each other. On half of the trials, foreknowledge about task repetition or task switch was available. On the other half, it was not. Endogenous preparation seems to involve lateral prefrontal cortex (BA 46/45) and posterior parietal cortex (BA 40). During preparation, higher activation increases in inferior lateral prefrontal cortex and superior posterior parietal cortex were associated with foreknowledge than with no foreknowledge. Exogenous adjustment seems to involve superior prefrontal cortex (BA 8) and posterior parietal cortex (BA 39/40) in general. During a task switch with no foreknowledge, activations in these areas were relatively higher than during a task repetition with no foreknowledge. These results suggest that endogenous preparation and exogenous adjustment for a task switch may be independent processes involving different brain areas.     

Hyperpolarization-activated graded persistent activity in the prefrontal cortex

We describe a phenomenon of hyperpolarization-activated graded persistent activity (HAGPA) in prefrontal cortex neurons. Successive hyperpolarizing pulses induced increasingly higher rates of tonic firing that remained stable for tens of seconds, allowing the neuron to retain a memory of the previous history of stimulation. This phenomenon occurred at the cellular level and in the absence of neuromodulators. Neurons with HAGPA had a sag during hyperpolarization, and blocking h-current eliminated the sag and prevented HAGPA, suggesting that the activation of this hyperpolarization-activated cationic current was necessary for the occurrence of the phenomenon. A single-neuron biophysical model including h-current modulation by intracellular calcium was able to display HAGPA. This form of neuronal memory not only allows the transformation of inhibition into an increase of firing rate, but also endows neurons with a mechanism to compute the properties of successive inputs into persistent activity, thus solving a difficult computational problem.     

Parallel processing of serial movements in prefrontal cortex

A key idea in Lashley's formulation of the problem of serial order in behavior is the postulated neural representation of all serial elements before the action begins. We studied this question by recording the activity of individual neurons simultaneously in small ensembles in prefrontal cortex while monkeys copied geometrical shapes shown on a screen. Monkeys drew the shapes as sequences of movement segments, and these segments were associated with distinct patterns of neuronal ensemble activity. Here we show that these patterns were present during the time preceding the actual drawing. The rank of the strength of representation of a segment in the neuronal population during this time, as assessed by discriminant analysis, predicted the serial position of the segment in the motor sequence. An analysis of errors in copying and their neural correlates supplied additional evidence for this code and provided a neural basis for Lashley's hypothesis that errors in motor sequences would be most likely to occur when executing elements that had prior representations of nearly equal strength.     

D2s dopamine receptor mediates phospholipase D and antiproliferation

The D2 dopamine receptor, short form (D2s) has been shown to stimulate phospholipase D (PLD) activity independent of activation of phospholipase C (PLC) activity in GH4 derived cells stably transfected with the D2s receptor [Mol. Pharm. 58 (2000) 455]. Agonist activation of D2s has been shown to mediate the inhibition of growth in the same cell line [J. Biol. Chem. 276 (1992) 24169; Endocrinology 134 (1994) 783]. In the present study, D2s-HEK 293 cells were generated using Epstein-Barr virus (EBV) based vectors. The stimulation of PLD by D2s can be augmented by the transfection of Rho A, but not Cdc 42 or Rac and nullified by transfection of N19 Rho A, a dominant negative form of Rho A. Addition of ethanol, at 0.5% reduced the ability of dopamine agonists to inhibit growth in D2s-HEK 293 cells, suggesting that PLD is involved in the antiproliferative effects of D2s signaling. In addition, the expression of N19 Rho A ablated the ability of the D2s to inhibit [3H]thymidine incorporation, while the expression of N19 Cdc 42 or N17 Rac had no effect. These results suggest that the D2s stimulation of PLD is Rho A dependent and lies along the signaling pathway which leads to the antiproliferative effects of D2s receptor activation.     

D1 and D2 dopamine receptor mRNA in rat brain.

Physiological and pharmacological criteria have divided dopamine receptors into D1 and D2 subtypes, and genes encoding these subtypes have recently been cloned. Based on the sequences of the cloned receptors, we prepared oligodeoxynucleotide probes to map the cellular expression of the corresponding mRNAs in rat brain by in situ hybridization histochemistry. These mRNAs showed largely overlapping yet distinct patterns of expression. The highest levels of expression for both mRNAs were observed in the caudate-putamen, nucleus accumbens, and olfactory tubercle. Within the caudate-putamen, 47 +/- 6% and 46 +/- 5% of the medium-sized neurons (10-15 microns) expressed the D1 and D2 mRNAs, respectively, and only the D2 mRNA was observed in the larger neurons (greater than 20 microns). The D1 and D2 mRNAs were expressed in most cortical regions, with the highest levels in the prefrontal and entorhinal cortices. Within neocortex, D1 mRNA was observed primarily in layer 6 and D2 mRNA in layers 4-5. Within the amygdala, D1 mRNA was observed in the intercalated nuclei, and D2 mRNA in the central nucleus. Within the hypothalamus, D1 mRNA was observed in the suprachiasmatic nucleus and D2 mRNA in many of the dopaminergic cell groups. Within the septum, globus pallidus, superior and inferior colliculi, mammillary bodies, and substantia nigra only D2 mRNA was detected. These data provide insight into the neuroanatomical basis of the differential effects of drugs that act on D1 or D2 receptors.     

Lateral prefrontal cortex contributes to maladaptive decisions

Humans consistently make suboptimal decisions involving random events, yet the underlying neural mechanisms remain elusive. Using functional MRI and a matching pennies game that captured subjects' increasing tendency to predict the break of a streak as it continued [i.e., the "gambler's fallacy" (GF)], we found that a strong blood oxygen level-dependent response in the left lateral prefrontal cortex (LPFC) to the current outcome preceded the use of the GF strategy 10 s later. Furthermore, anodal transcranial direct current stimulation over the left LPFC, which enhances neuronal firing rates and cerebral excitability, increased the use of the GF strategy, and made the decisions more "sticky." These results reveal a causal role of the LPFC in implementing suboptimal decision strategy guided by false world models, especially when such strategy requires great resources for cognitive control.     

Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors

To address the role of D1 receptors in the medial prefrontal cortex, we combined pharmacological and genetic manipulations to examine long-term synaptic potentiation (LTP)/long-term synaptic depression (LTD) in brain slices of rats and mice. We found that the D1 antagonist SCH23390 selectively blocked the maintenance but not the induction of LTP in the prefrontal cortex. Conversely, activation of D1 receptors facilitated the maintenance of LTP, and this effect is impaired in heterozygous D1 receptor knockout mice. Low-frequency stimulation induced a transient depression in the medial prefrontal cortex. This depression could be transformed into LTD by coapplication of dopamine. Coapplication of dopamine, however, shows no facilitating effect on LTD in heterozygous D1 receptor knockout mice. These results provide pharmacological and genetic evidence for a role of D1 receptors in the bidirectional modulation of synaptic plasticity in the medial prefrontal cortex. The absence of this modulation in heterozygous knockout mice shows that a dysregulation of dopamine receptor expression levels can have dramatic effects on synaptic plasticity in the prefrontal cortex.     

Anticipation of conflict monitoring in the anterior cingulate cortex and the prefrontal cortex

The anterior cingulate cortex (ACC) has been suggested as a monitoring center that is responsible for online detection of response conflicts. In this view, the conflict signal detected by the ACC is transmitted to other brain regions, such as the dorsal part of the lateral prefrontal cortex (lPFC), to increase the level of cognitive control. In this functional MRI (fMRI) study, we examined the conflict resolution that goes beyond online detection of response conflicts. Participants learned pseudoarithmetic problem-solving tasks that involve stimulus-response mapping rules with high or low conflicts. On half of the trials, participants had a preview of the upcoming operator that allowed advance preparation for the mapping rules. The preview significantly reduced the conflict effects on latency. During the preview, both the ACC and lPFC were activated in anticipation of conflict, and this anticipatory activation was highly predictive of the subsequent latency. These results suggest that the ACC and lPFC are responsible for both anticipatory preparation and online adjustment in response to conflicts. The results also confirm the roles of the lPFC and ACC in managing conflict during problem solving and extend these roles to include responding to anticipation of conflicts that may arise between incompatible stimulus-response mappings maintained in working memory during preparation.     

Memory fields of neurons in the primate prefrontal cortex

Many prefrontal (PF) neurons convey information about both an object’s identity (what) and its location (where). To explore how they represent conjunctions of what and where, we explored the receptive fields of their mnemonic activity (i.e., their “memory fields”) by requiring monkeys to remember both an object and its location at many positions throughout a wide portion of central vision. Many PF neurons conveyed object information and had highly localized memory fields that emphasized the contralateral, but not necessarily foveal, visual field. These results indicate that PF neurons can simultaneously convey precise location and object information and thus may play a role in constructing a unified representation of a visual scene.