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fMRI Zooms Down on Source of Dopaminergic Projections

10 April 2008. In a first for neuroimaging, a Princeton University research team has overcome technical obstacles to successfully measure blood oxygen level dependent (BOLD) responses in the ventral tegmental area (VTA). This small brainstem nucleus is of great interest to schizophrenia researchers—dopaminergic VTA axons project to the ventral striatum (VStr) to form the brain’s “reward circuit” (the mesolimbic dopamine system) and also to the prefrontal cortex (PFC; the mesocortical dopamine system), where they regulate functions such as working memory. Dysfunction in the dopaminergic systems originating in the VTA has been implicated in schizophrenia, not to mention addiction, depression, and other psychiatric disorders (see the Dopamine Hypothesis of Schizophrenia by Anissa Abi-Dargham).

As reported in the February 29 issue of Science, functional magnetic resonance imaging (fMRI) studies of dopaminergic circuits have so far been restricted to VStr and PFC because these structures are large enough to reliably produce BOLD signals using conventional fMRI techniques, which attain a spatial resolution of several millimeters per voxel. The VTA is only about 60 cubic millimeters, or two voxels, in volume. The imaging challenge presented by the small size of these nuclei is compounded by the several large, pulsatile arteries that supply the brainstem with blood. With each beat of the heart, the tiny brainstem nuclei shift sufficiently in space to create troublesome movement artifacts. Moreover, differences in brainstem anatomy across individuals have made it difficult to precisely align, or “register,” brainstem structures in data sets used for group analyses.

Complementary innovations at Princeton’s Neuroscience Institute (PNI) allowed first author Kimberlee D’Ardenne, PNI co-director Jonathan Cohen, Leigh Nystrom, and Samuel McClure, now at Stanford University, to precisely locate the VTA and to easily differentiate it from other nuclei, to control for cardiac-related artifacts, and to precisely register their data across subjects. The team observed clear BOLD signals that reflected the study participants’ expectations of rewards, a finding that dovetails with a “reward prediction error theory” of dopamine function derived from single-unit recording studies in nonhuman primates.

In this previous work on reward prediction error, Wolfram Schultz and colleagues trained monkeys in a classical conditioning procedure in which the monkeys learned to expect a juice reward at a fixed interval after the display of a visual cue (reviewed in Schultz et al., 1997). Before training, VTA neurons increased their firing immediately after the delivery of a reward; this was termed a “positive reward prediction error” because the reward was unexpected, and hence not predicted. After training, VTA neurons increased firing just after presentation of the visual cue, and subsided to baseline firing levels by the time the reward was provided; here, the reward was predicted correctly. However, if a reward was not presented at the expected interval, a “negative reward prediction error” occurred: VTA neurons increased their firing after the visual cue and returned to baseline, but then markedly reduced their firing just after the time the reward was expected. Schultz and colleagues concluded that “dopaminergic activity encodes expectations about external stimuli or reward.”

The Princeton group studied a group of thirsty humans in an adaptation of this procedure that allowed for measurement of both positive and negative reward prediction errors after training. By sometimes delaying the delivery of juice or water rewards to subjects, the group was able to create conditions in which an expected reward was delivered at an unexpected time, hence eliciting a negative prediction error followed by a positive prediction error.

In high-resolution proton-density weighted images, the bow-shaped substantia nigra, another brainstem dopaminergic structure, was clearly visible, and provided a landmark to accurately locate the triangular VTA along the brain’s midline for fMRI. Functional imaging was synchronized with the subjects’ pulse, and using a new normalization algorithm, BOLD signals from the VTA could be properly registered anatomically, despite the varying brainstem anatomy of the subjects.

The researchers found that the BOLD signal in the VTA was significantly related to positive, but not negative, reward prediction errors. Conversely, the BOLD signal in the VStr was significantly related to negative reward prediction errors. However, there was a positive correlation between the VTA and VStr BOLD response to unexpected rewards, indicating that the VTA positive prediction error signal influences the BOLD signal in VStr.

To ensure that these findings apply to different types of rewards, the researchers conducted a second set of experiments in which subjects were presented with a number from 0 to 10 and asked to guess if a subsequently presented number would be larger or smaller. For each correct guess, the subjects were given $1.00. Again, the VTA BOLD responses reflected a positive reward prediction error, and there was good anatomical overlap between the VTA regions activated by juice or water and those activated by a monetary reward.

The Princeton group says that their work is generalizable in other ways as well, for example, to other small brainstem nuclei that contain serotonergic and noradrenergic neurons, which bodes well for future fMRI research on the role of monoaminergic modulatory systems in psychiatric illness.—Peter Farley.

Reference:
D’Ardenne K, McClure SM, Nystrom LE, Cohen JD. BOLD responses reflecting dopaminergic signals in the human ventral tegmental area. Science. 2008 Feb 29;319 (5867):1264-7. Abstract

Comments on Related News


Related News: Dopamine D2 Receptors Accentuate the Positive ... and the Cognitive?

Comment by:  Barbara K. Lipska
Submitted 20 February 2006
Posted 20 February 2006

Kellendonk et al. have reported that transient and selective overexpression of dopamine D2 receptors in the mouse striatum during development has long-term effects on cognitive function mediated by the prefrontal cortex. This is an important study providing further elegant evidence that disturbed function of the subcortical dopamine system may affect dopamine functioning in the entire circuitry and have important adverse behavioral consequences. It is unclear, however, whether this mouse model provides us with new clues about the pathophysiology of schizophrenia. A hyperdopaminergic hypothesis of schizophrenia originated from pharmacological studies showing that dopamine D2 antagonists have antipsychotic efficacy and dopamine agonists, such as amphetamine or apomorphine, can induce psychosis (Randrup and Munkvad, 1974; Snyder, 1972). This hypothesis has been supported recently by clinical data from brain imaging studies with D2 receptor ligands showing higher presynaptic dopamine terminal activity in at least acutely psychotic patients when challenged with amphetamine or at baseline (Abi-Dargham et al., 2000; Hietala et al., 1994). Accordingly, amphetamine or apomorphine-induced hyperactivity and stereotypy in rodents have been postulated as psychosis-like behaviors and such pharmacological models have been widely used for screening antipsychotic drugs. Currently, all antipsychotic drugs on the market act by reducing D2 signals in brain, most by functioning as antagonists of D2 receptors. It is also clear, however, that although these drugs are beneficial, they do not cure the disease. It is also increasingly clear that although there is considerable evidence about the role of the dopaminergic system in the pathophysiology of schizophrenia, genetic association and linkage between schizophrenia and the genes encoding dopamine receptors or transporter remain weak (Daniels et al., 1995; Kojima et al., 1999). Thus, dopamine abnormalities may not be at the core of pathophysiology. The exploration of genetic models beyond the dopamine system may perhaps prove more fruitful for capturing many aspects of this devastating illness.

References:

Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8104-9. Abstract

Daniels J, Williams J, Asherson P, McGuffin P, Owen M. No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT). Am J Med Genet. 1995 Feb 27;60(1):85-7. Abstract

Hietala J, Syvalahti E, Vuorio K, Nagren K, Lehikoinen P, Ruotsalainen U, Rakkolainen V, Lehtinen V, Wegelius U. Striatal D2 dopamine receptor characteristics in neuroleptic-naive schizophrenic patients studied with positron emission tomography. Arch Gen Psychiatry. 1994 Feb;51(2):116-23. Abstract

Kojima H, Ohmori O, Shinkai T, Terao T, Suzuki T, Abe K. Dopamine D1 receptor gene polymorphism and schizophrenia in Japan. Am J Med Genet. 1999 Apr 16;88(2):116-9. Abstract

Randrup A, Munkvad I. Pharmacology and physiology of stereotyped behavior. J Psychiatr Res. 1974;11:1-10. Review. No abstract available. Abstract

Snyder SH. Catecholamines in the brain as mediators of amphetamine psychosis. Arch Gen Psychiatry. 1972 Aug;27(2):169-79. Review. No abstract available. Abstract

View all comments by Barbara K. Lipska

Related News: Dopamine D2 Receptors Accentuate the Positive ... and the Cognitive?

Comment by:  Stephen J. Glatt
Submitted 26 February 2006
Posted 27 February 2006
  I recommend the Primary Papers

The development of animal models is a critical need in the realm of schizophrenia research. Current models relying on lesions or pharmacological manipulations may be relatively nonspecific, and thus, less than optimal for unraveling the underlying pathophysiology of the disorder. Models in which specific key candidate genes are up- or down-regulated may be better models because the effects can be more subtle and, as in this study, a very specific behavioral deficit may result. Ultimately, many genes, including DRD2, may be involved in discrete aspects of the illness, and when those gene deficiencies co-occur in certain individuals, schizophrenia may manifest. This study developed and validated a model, but the study itself is a model for how such studies should be done.

View all comments by Stephen J. Glatt

Related News: Dopamine D2 Receptors Accentuate the Positive ... and the Cognitive?

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 27 February 2006
Posted 27 February 2006

The study by Kellendonk and colleagues from Eric Kandel’s lab at Columbia is a landmark piece of science in a number of respects. Transgenic overexpression of D2 receptors in the mouse striatum is a novel model of how a developmental perturbation in striatal dopaminergic signaling has long-term implications for processing of information through critical brain circuits involved in learning and memory. The model may also have implications for understanding abnormalities of the function of this circuit in schizophrenia. There is ample evidence from clinical and from postmortem studies that cortical-striatal circuits are involved as part of the pathophysiology of schizophrenia. The work of Ann Marie Thierry and colleagues in Paris in the 1970s first drew attention to the fact that cortical function impacted on the striatal dopamine system (Thierry et al., 1973). A ground-breaking study of Pycock et al. (1980) showed that DA depletion in the prefrontal cortex affected DA parameters in the striatum, by increasing specifically DA turnover and D2 receptor expression. They were the first to report an inverse relationship between cortical and subcortical DA activity, a finding that has been reproduced in a broad variety of studies in rodents, nonhuman primates, and in humans (e.g., Jaskiw et al., 1990; 1991; Deutch, 1993; Saunders et al., 1998; Bertolino et al., 1999; 2000; Meyer-Lindenberg et al., 2002; 2005). The mechanism of this effect is still uncertain, but likely involves the anatomical connectivity between prefrontal cortex and brainstem DA neurons, which involve a tonic inhibitory brake, such that normal prefrontal cortical function translates into tonic inhibition of DA neurons that project to the striatum (Carr and Sesack, 2000). Thus, prefrontal cortex is in a position to release that brake and increase DA-related reinforcement of environmental stimuli, when circumstances dictate an appropriately DA response, as might be expected during learning and memory. It is tempting to conclude from these various experiments over 30 years that the prefrontal cortex regulates the reward/reinforcement effects of DA neurons based on experiential context. The studies beginning with Thierry showed that when prefrontal function was disturbed, DA activity was no longer appropriately regulated. The study of Kellendonk et al. is consistent in terms of the circuitry involved with these earlier studies, but instead of creating an abnormality at the level of the prefrontal cortex and disrupting regulation of the DA reward system, they changed DA function directly in the striatum and their behavioral readout suggested that abnormal function of prefrontal cortex was a result. The “yin-yang” relationship again was reproduced, but now starting with the yang rather than the yin. The yang-based mechanism of the striatal effect on cortical function and cortical DA turnover is likely complex, including via striatal feedback to mesencephalic DA neurons that project to cortex and via striatal projections through thalamus back to prefrontal cortex.

The findings of Kellendonk et al. illustrate how critical prefronto-centric circuitry is, especially during development, for the elaboration of behaviors and biochemical phenomena related to schizophrenia. Their important finding that restoring normal DA function in the striatum did not restore prefrontal cognition indicates that it was no longer a matter of acute excess D2 activity in the striatum that accounted for the cognitive abnormalities. Presumably, in developmentally wiring the circuitry in and out of prefrontal cortex, abnormal information processing through the striatum (which feeds back to prefrontal cortex and presumably formats cortical information for frontally mediated action) changes the wiring diagram, producing more trait-like functional abnormalities. Trait-like changes in prefrontal function and molecular biology related to early developmental perturbations of other prefronto-centric neuronal systems implicated in schizophrenia, for example, temporal-limbic inputs to prefrontal cortex, also have been described (see Lipska and Weinberger, 2000, for review).

Finally, the study has important implications for neurobiologic models of phenomena associated with schizophrenia. PET studies of patients with schizophrenia suggest that, to the extent that striatal DA activity may be increased (Abi-Dargham et al., 1998), it is a state phenomenon, linked to active psychosis. On the other hand, evidence of abnormal cortical DA activity and function is more trait-like and persists between periods of florid psychosis. The persistent changes in cortical function independent of fluctuations in striatal D2 expression may provide some parallels to the clinical phenomena. It is surprising that these animals showed no deficits in activity or in prepulse inhibition of startle, both of which have been interpreted as measures of excess DA activity and as animal correlates of psychosis. The failure to observe these phenomena may be related to species differences—here mice as compared to earlier models with rats—or it may reflect relatively more selective overexpression of D2 receptors in the dorsal striatum. This latter finding is of interest as recent studies from Laurelle and colleagues at Columbia, using high-resolution PET imaging, have found that increased DA activity in patients with schizophrenia may also involve preferentially the dorsal striatum. The changes in DA measures in the cortex also bear interesting relationships to those found in patients with schizophrenia. The transgenic mice showed no change in markers of cortical DA innervation, which has been reported in schizophrenia (Akil et al., 1999), but they did show reduced cortical DA turnover, evidence of which also has been reported in schizophrenia (Weinberger et al., 1988). During D2 overexpression, D1 receptor sensitivity appeared to be increased, but during normalization of D2 overexpression, D1 receptors in prefrontal cortex appeared to be functionally subsensitive. These variations in cortical DA function may correspond to apparent reduced cortical DA activity as a trait characteristic and enhanced cortical DA activity as a correlate of acute psychosis (Winterer and Weinberger, 2004).

References:

Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry. 1998 Jun;155(6):761-7. Abstract

Akil M, Pierri JN, Whitehead RE, Edgar CL, Mohila C, Sampson AR, Lewis DA. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry. 1999 Oct;156(10):1580-9. Abstract

Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology. 2000 Feb;22(2):125-32. Abstract

Bertolino A, Knable MB, Saunders RC, Callicott JH, Kolachana B, Mattay VS, Bachevalier J, Frank JA, Egan M, Weinberger DR. The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia. Biol Psychiatry. 1999 Mar 15;45(6):660-7. Abstract

Carr DB, Sesack SR. Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci. 2000 May 15;20(10):3864-73. Abstract

Deutch AY. Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease. J Neural Transm Gen Sect. 1993;91(2-3):197-221. Review. Abstract

Jaskiw GE, Karoum F, Freed WJ, Phillips I, Kleinman JE, Weinberger DR. Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat. Brain Res. 1990 Nov 26;534(1-2):263-72. Abstract

Jaskiw GE, Weinberger DR, Crawley JN. Microinjection of apomorphine into the prefrontal cortex of the rat reduces dopamine metabolite concentrations in microdialysate from the caudate nucleus. Biol Psychiatry. 1991 Apr 1;29(7):703-6. No abstract available. Abstract

Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology. 2000 Sep;23(3):223-39. Review. Abstract

Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002 Mar;5(3):267-71. Abstract

Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005 May;8(5):594-6. Epub 2005 Apr 10. Abstract

Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature. 1980 Jul 3;286(5768):74-6. No abstract available. Abstract

Saunders RC, Kolachana BS, Bachevalier J, Weinberger DR. Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine. Nature. 1998 May 14;393(6681):169-71. Abstract

Thierry AM, Blanc G, Sobel A, Stinus L, Golwinski J. Dopaminergic terminals in the rat cortex. Science. 1973 Nov 2;182(4111):499-501. No abstract available. Abstract

Weinberger DR, Berman KF, Illowsky BP. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry. 1988 Jul;45(7):609-15. Abstract

Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci. 2004 Nov;27(11):683-90. Review. Abstract

View all comments by Daniel Weinberger

Related News: Dopamine D2 Receptors Accentuate the Positive ... and the Cognitive?

Comment by:  Ricardo Ramirez
Submitted 28 February 2006
Posted 28 February 2006

I read the paper by Simpson et al. from Kandel's group with much interest. It seems that the dopamine hypothesis of schizophrenia has many lives and appears and reappears in many forms. This latest reincarnation combines hyperdopaminergia with the neurodevelopmental hypothesis of the disorder. My initial enthusiasm, however, waned upon closer reading of the paper.

It seems that the various conclusions reached are not wholly supported by the results. The prefrontal cognitive deficits of the D2 mice seem to be extremely subtle. It is difficult to infer specific impairments of working memory performance solely from acquisition effects. The D2 mice require more trials to reach criteria, but how do the mice perform once these criteria are met? To be sure, schizophrenia patients present with learning impairments, but their working memory deficits are persistent and ever present. It is interesting that high-order “executive functions” as measured by attentional set-shifting (e.g., intra- and extra-dimensional shifts) are spared in these mice, given that these depend on the rodent medial frontal cortex and are modulated by dopamine as well (Birrell and Brown, 2000; Tunbridge et al., 2004). Thus, contrary to what has been reported, these mice show normal behavioral flexibility. We are thus left with mice whose prefrontal function, at least behaviorally, is relatively intact.

A more pressing issue is the controls that were used for the experiments. The authors did not compare D2 mice (carrying both transgenes) with mice carrying the same two transgenes but who did not at any time express the D2 receptor. Instead the authors compared the D2R expressing mice with their littermates who carried no transgene or either the CamKII or D2 transgenes alone. They state that these groups showed no differences, but their control groups were of nine mice, so there is a potential lack of power to detect any differences between these groups. It will be of interest to know whether any of the other striatal D2 overexpressing lines that were created show similar phenotypes. Lacking this information, we cannot be sure that the subtle effect on behavior is not due to the disruption of another gene by the random insertion of the D2 transgene.

This paper is a natural extension of many years of work showing the balance between cortical and subcortical dopamine systems (Grace, 1991). A brief transient overexpression of striatal D2Rs during development does seem to affect DA function long into adulthood. This mouse model also reflects the long-used strategy of probing those systems thought to underlie the pathophysiology of schizophrenia. These models are of great benefit, but whether they shed any light on the cause or etiology of the disorder is an open question. One would hope that with these now sophisticated genetic tools and the identification of several reliable susceptibility genes (NRG1, DTNBP1, DISC1), more etiologically relevant mouse models can be created.

References:
Birrell JM and Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000 Jun 1;20(11):4320-4. Abstract Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience. 1991;41(1):1-24. Abstract Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5. Abstract

View all comments by Ricardo Ramirez

Related News: Dopamine D2 Receptors Accentuate the Positive ... and the Cognitive?

Comment by:  Tomiki SumiyoshiPhilip Seeman (Disclosure)
Submitted 7 March 2006
Posted 8 March 2006
  I recommend the Primary Papers

Comment by Tomiki Sumiyoshi and Philip Seeman
Kellendonk et al. report various behavioral and neurochemical findings from transgenic mice expressing an increased number of dopamine (DA)-D2 receptors in the striatum, labeled by 3H-spiperone. These mice showed deficits in some aspects of working memory, a cognitive domain associated with the prefrontal cortex function.

This study was prompted by the landmark hypothesis that DA supersensitivity in some of the subcortical brain regions, such as the striatum, constitutes a neurochemical basis for psychotic symptoms of schizophrenia (e.g., van Rossum, 1966; Seeman et al., 2005). Conventionally, dysregulation of DA-related behaviors, including enhanced locomotor activity and stereotypy, as well as disrupted prepulse inhibition, have been thought to reflect psychosis-related symptoms. However, the D2 receptor transgenic mice did not demonstrate alterations in any of these behavioral measures, although an in vitro assay indicated reduced DA-induced adenylate cyclase activity in these animals. To follow the behavioral changes after challenging the mice with amphetamine or other DA-agonists would have conveyed more information on whether the up-regulated D2 receptors are actually functional.

It is also crucial to determine if there is a shift of D2 receptors to the high-affinity state, or functional state (D2High) (Seeman et al., 2005), in this animal model of schizophrenia. It is argued that D2High sites may be more relevant to psychotic symptoms than the total density of D2 receptors measured by conventional binding methods, such as that used by Kellendonk et al. with 3H-spiperone as a ligand (Seeman et al., 2005; Sumiyoshi et al., 2005). In fact, increased proportions of D2High have been reported in various animal models of psychosis, including those based on the neurodevelopmental hypothesis of schizophrenia (Seeman et al., 2005; Sumiyoshi et al., 2005).

Kellendonk et al. found that the extra D2 receptors in the striatum were associated with the cognitive disturbances. Since it has been found that overexpression of the catechol-O-methyl transferase (COMT) gene also impairs cognitive function (Chen et al., 2005), further research is needed to determine if the cognitive deficits result from overexpression of these specific genes and not just any gene.

References:

van Rossum JM. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther. 1966 Apr;160(2):492-4. No abstract available. Abstract

Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Mannisto PT, Robinson S, Palmiter RD, Tallerico T. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3513-8. Epub 2005 Feb 16. Abstract

Sumiyoshi T, Seeman P, Uehara T, Itoh H, Tsunoda M, Kurachi M. Increased proportion of high-affinity dopamine D2 receptors in rats with excitotoxic damage of the entorhinal cortex, an animal model of schizophrenia. Brain Res Mol Brain Res. 2005 Oct 31;140(1-2):116-9. Epub 2005 Jul 28. Abstract

Chen J, Lipska BK, Weinberger DR. New genetic mouse models of schizophrenia: Mimicking cognitive dysfunction by altering susceptibility gene expression. Neuropsychopharmacology. 2005; 30 (Suppl 1):S12-13.

View all comments by Tomiki Sumiyoshi
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Comment by:  Patricia Estani
Submitted 7 March 2006
Posted 8 March 2006
  I recommend the Primary Papers

I agree with Dr Weinberger's comments about the work of Kellendonk et al. In this sense, the cortical, frontal-striatal connections are well-known circuits involved in the development of schizophrenia.

Dr. Weinberger, in 1992, reported studies from limbic-prefrontal circuits, connections involved in schizophrenia pathophysiology (Weinberger et al., 1992). This work used an inverse experimental methodology (of corroborating the existing relationship between frontal cortex and the striatum) from the methodology commonly used (search for the line-activation in frontal cortex, then see the results in the striatum).

The most outstanding part of the study is one dedicated to the developmental approach. Thus, in the article, it was clear that restoring the normal DA function in the striatum did not restore cognitive functioning. As this article demonstrates, developmental approaches are excellent for the understanding of the neurobiology of schizophrenia.

References:

Weinberger DR, Berman KF, Suddath R, Torrey EF. Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry. 1992 Jul;149(7):890-7. Abstract

View all comments by Patricia Estani

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Andreas Meyer-Lindenberg
Submitted 15 May 2006
Posted 15 May 2006
  I recommend the Primary Papers

I think this is an interesting paper, as it shows that alterations in tonic dopaminergic stimulation can result in a pronounced and qualitative switch (LTD to LTP) in the behavior of prefrontal neurons. Although the concept of tonic versus phasic dopaminergic stimulation has been adopted widely by the schizophrenia research community, the majority of the preclinical work has focused on acute changes in dopamine concentration and on subcortical structures, especially the nucleus accumbens, and from my perspective as a clinical researcher, it is welcome to see some data that extend to prefrontal cortex and longer timescales, although it must be emphasized that this paper concerns results from rats, in slices in vitro, using tetanic stimulation, and that the pretreatment with dopamine lasted for 40 minutes only. With these caveats, it is exciting to see that pretreatment with dopamine after what the authors presume is a 4-hour period of neurotransmitter depletion during slice preparation produces LTP after a weak tetanic stimulus, compared to LTD that the same stimulus evoked without dopamine priming. Since LTD arose under conditions of relative dopamine depletion, which might reflect, at least in directionality, the situation in schizophrenia, these data suggest that functionally impairing qualitative changes in a neuronal response in prefrontal cortex of relevance for working memory function could result from quantitative reductions in extracellular (tonic) dopamine content. It is also of interest that the authors demonstrate that the LTP requires concurrent stimulation of metabotropic glutamate receptors, suggesting a mechanism by which widely studied risk genes for schizophrenia such as COMT and GRM3 could interact in impairing prefrontal cortex function.

View all comments by Andreas Meyer-Lindenberg

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Patricia Estani
Submitted 3 June 2006
Posted 3 June 2006
  I recommend the Primary Papers

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Terry Goldberg
Submitted 20 June 2006
Posted 20 June 2006

Matsuda et al. demonstrate that priming D1 and D2 receptors may induce LTP; otherwise, LTD develops. To elaborate, a weak tetanic stimulation and dopamine stimulation produces LTD. However, if dopamine is perfused for 12 to 40 minutes at D1 and D2 receptors and a tetanic stimulus is provided, LTP, a form of cellular learning associated with memory, develops. This study has potentially important implications for understanding the cause of prefrontally based failures in information processing in schizophrenia. It gives additional weight to arguments that reduced dopaminergic tone at the cortical level is responsible for at least some of the cognitive problems associated with the disorder.

It also helps make sense out of some otherwise anomalous data in the literature. For instance, in manipulations of several tests of purported attentional control and vigilance problems, findings appeared more consistent with difficulties in constructing a representation than with attention per se in target detection (e.g., Elvevag et al., 2000; Fuller et al., 2005).

One thing that I would certainly give an eyetooth to know is how the authors view their work in light of findings by Seamans and Goldman-Rakic on differences in the consequences of stimulation of D1 and D2 receptors (simplistically, that D1 activation promotes task-relevant information, while D2 stimulation may produce task-irrelevant information processing experienced as interference).

Caveat Emptor: I don’t have the expertise to comment on the slice preparation methodology.

References:

Elvevag B, Weinberger DR, Suter JC, Goldberg TE. Continuous performance test and schizophrenia: a test of stimulus response compatibility, working memory, response readiness, or none of the above? Am J Psychioatry 2000; 157:772-780. Abstract

Fuller RL, Luck SJ, McMahon RP, Gold JM. Working memory consolidation is abnormally slow in schizophrenia. J Abnorm Psychol 2005; 114:279-290. Abstract

View all comments by Terry Goldberg

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Satoru Otani
Submitted 22 July 2006
Posted 24 July 2006

In his June 20 comment, Dr. Goldberg raised an important question concerning our paper: how our results, showing the necessity of D1+D2 receptor coactivation for prefrontal LTP induction and priming, fit into the scheme proposed by Seamans et al., 2001, that is, the differential roles played by D1 and D2 receptors for prefrontal cortex (PFC) cognitive processes.

I think I have to first point out that the dependency of PFC long-term potentiation (LTP) induction (let alone "priming" now) on DA receptor subtypes may vary among subpopulations of PFC synapses. In ventral hippocampus (HC)-PFC synapses, LTP induction requires D1 but not D2 receptors (Gurden et al., 2000). This in vivo study fits with the idea that HC-PFC projection and its D1 receptor-mediated modulation are critical in spatial information processing (working memory) and encoding of this information. However, recent in vivo results of Yukiori Goto at the University of Pittsburgh (personal communication, but see Goto and Grace, 2005) indicate that LTP induction in cortico-cortical synapses in the PFC may be dependent on both D1 and D2 receptors, similar to our case. Dr. Goto found that while synaptic potentiation in the HC-PFC synapses indeed depends only on D1 receptors, potentiation in cortico-cortical synapses, stimulated by the electrode inserted in the superficial layer of the PFC as in our preparation, depends on the activation of both D1 and D2 receptors. Thus, it appears that DA receptor dependency of LTP induction differs between the HC projection input and the cortico-cortical input—the former dependent only on D1 receptors and the latter on D1+D2 receptors.

How significant this difference might be functionally is, of course, still an issue for speculation. It seems clear that working memory input from the HC (and strengthening of this input), which may depend only on D1 receptors, are critical for PFC cognitive function. But also, other cortical inputs, which are not necessarily related to the attention-driven working memory, may be as critical for the formation and achievement of goal-directed behavior, and strengthening of these cortical inputs may depend on D1+D2 receptors. Incidentally, Dr Goto also showed that the organization of a planned behavior tested in a modified radial-arm maze task requires not only intact HC-PFC connection but also the activation of both D1 and D2 receptors within the PFC (Goto and Grace, 2005). We are tempted to suggest that neuronal traces within the PFC necessary for the generation of goal-directed behavior may be heterogeneous both in their input origin and in their formation mechanism.

References:

Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21, 3628-3638. Abstract

Gurden H, Takita M, Jay TM. Essential role of D1 but not D2receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J Neurosci. 2000 Nov 15;20(22):RC106. Abstract

Goto Y, Grace AA (2005) Retrospective and prospective memory processing in the hippocampal—prefrontal cortical network. Soc Neurosci Abstr 413.3.

View all comments by Satoru Otani

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Jeremy Seamans
Submitted 26 July 2006
Posted 27 July 2006

Drs. Goldberg and Otani raise some excellent points in their comments on the Matsuda et al. paper. As Dr. Otani alluded to in his latest comment, it is useful to define exactly what is being modulated under different experimental conditions and how this all relates to prefrontal cortex (PFC) function in general.

Dr Otani’s studies investigate synaptic plasticity induced by tetanic stimulation and how this process is modulated by tonic dopamine (DA). Long-term potentiation/long-term depression (LTP/LTD) induced by tetanic stimulation has provided us with perhaps the best model of the cellular basis of long-term memory and has been proposed to underlie, among other things, various aspects of long-term spatial memory and declarative memory. LTP is a long-lasting, passive, associational memory mechanism, unlike working memory that is transient in nature, relies on active processing and is not associational. Therefore, in PFC, it would be highly unlikely that LTP/LTD is the neural mechanism of working memory. However, to solve a working memory problem, one must manipulate newly acquired information within a certain context or based on a pre-learned rule. Perhaps the best example of how these processes relate can be found in White and Wise, 1999, and Wallis et al., 2001, who investigated the activation of PFC neurons in situations where two different abstract rules could be applied. PFC neurons showed different degrees of activation during a delay period depending on the preference of the neuron for a specific task rule. Therefore, stable long-standing rules regulate how strongly a cell in PFC exhibits short-term memory related activity. These rules were learned over time and were stable. LTP/LTD are as good mechanisms as any for their cellular basis. This implies that LTP/LTD-like mechanisms influenced the manner in which PFC neurons exhibited transient working memory related activity. Therefore, as shown by Matsuda et al. and suggested by others (e.g., Lisman and Grace, 2005), a long-term memory mechanism, perhaps involved in the formation of stable rules, is subjected to modulation by tonic and phasic DA. This long-term memory in turn regulates the online active processing of information in working memory.

In contrast, many investigators have proposed that DA is also able to directly modulate working memory related activity. As noted by Dr. Goldberg, in addition, we have suggested that the mode of modulation is different for D1 and D2 receptors in PFC. Like task rules, DA appears to modify the strength of delay-period activity (e.g., Sawaguchi, 2001). Furthermore, the modulation of synaptic currents by DA, especially via D1 receptors, is very long-lasting and has been termed “late potentiation” and in fact shares aspects of the late phase of LTP (Huang and Kandel, 1995). However, unlike stable task rules, DA levels can change quickly and dynamically, and as a result, delay-period activity may be increased or decreased depending on the level of DA and the differential activation of D1 and D2 receptors, even if the same task rule is being implemented. The dynamic modulation of DA levels depends on a variety of factors such as intrinsic motivation, stress, and even the strength of the active memory trace (Phillips et al., 2004).

Therefore, DA modulates LTP/LTD, which in turn may be involved in the rule-dependent modification of delay-period activity. DA can also directly modulate the ionic currents involved in actually generating delay-period activity. Although this modulation can be long-lasting, DA levels and activation of different DA receptors change dynamically and the mode of modulation could continuously vary based on a variety of intrinsic and task-dependent variables.

Perhaps one implication of all this for schizophrenia would be that dysfunction of DA-dependent modulation of LTP/LTD would lead to an inability to accurately store or implement the appropriate rule for a given situation. In contrast, dysfunction of the direct DA modulation of ionic and synaptic currents could lead to more immediate issues such as distractability or pathologically focused processing of information within working memory (Seamans et al., 2001; Seamans and Yang, 2004).

References:

Huang YY, Kandel ER. D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2446-50. Abstract

Lisman JE, Grace AA. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron. 2005 Jun 2;46(5):703-13. Review. Abstract

Phillips AG, Ahn S, Floresco SB. Magnitude of dopamine release in medial prefrontal cortex predicts accuracy of memory on a delayed response task. J Neurosci. 2004 Jan 14;24(2):547-53. Abstract

Sawaguchi T. The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task. Neurosci Res. 2001 Oct;41(2):115-28. Abstract

Seamans JK, Gorelova N, Durstewitz D, Yang CR. Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci. 2001 May 15;21(10):3628-38. Abstract

Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004 Sep;74(1):1-58. Review. Erratum in: Prog Neurobiol. 2004 Dec;74(5):321. Abstract

Wallis JD, Anderson KC, Miller EK. Single neurons in prefrontal cortex encode abstract rules. Nature. 2001 Jun 21;411(6840):953-6. Abstract

White IM, Wise SP. Rule-dependent neuronal activity in the prefrontal cortex. Exp Brain Res. 1999 Jun;126(3):315-35. Abstract

View all comments by Jeremy Seamans

Related News: Dopamine Problems? Blame the Hippocampus

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 29 November 2007
Posted 29 November 2007

What struck me most about the paper of Lodge and Grace is the overall consistency of the body of work between the preclinical and clinical observations, even down to the effect size for the dopaminergic alteration. Dopamine release in schizophrenia is at least double that in controls; whether measured after amphetamine (on average 17 percent displacement of the benzamide radiotracer versus 7 percent in controls) (Laruelle et al., 1999) or at baseline (19 percent D2 occupancy by dopamine in patients versus 9 percent in controls) (Abi-Dargham et al., 2000), the increase in dopamine activity in VTA of the MAM rats reported here is also a doubling of what is measured in saline-treated rats.

This work presents an important contribution to the field because it clarifies the role of the hippocampus in one of the cardinal features of the disorder as modeled in MAM rats. The fact that MAM treatment is one of the most valid animal models of schizophrenia—it replicates many of the disturbances, neurochemical, cellular, dendritic, morphometric, and behavioral, observed in schizophrenia—makes the finding very compelling.

The role of an abnormal hippocampal node in an important circuit central to the pathophysiology of schizophrenia has face validity: there are now many converging lines of evidence in patients with schizophrenia for alterations in hippocampal volume, cytoarchitecture, function, and neurochemical indices. What this paper presents that is unique is evidence, in a valid model of schizophrenia, for an etiological link between the faulty hippocampus and the faulty VTA. The next step will be to test an association between pathology of the hippocampus and that of the VTA and related striatal output in patients with schizophrenia. This is a study we currently are conducting, and is an example of translational research where a theory gets support and contributions by going back and forth between preclinical and clinical testing. If there is an association in the same patients between the hippocampal pathology and dopamine dysregulation, it will suggest that what is described for the MAM model here may be true for schizophrenia, too, i.e., that the pathology of the dopamine system is driven by a faulty hippocampal input.

References:

Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46:56-72. Abstract

Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97:8104-8109. Abstract

View all comments by Anissa Abi-Dargham

Related News: Dopamine Problems? Blame the Hippocampus

Comment by:  Elizabeth Tunbridge
Submitted 20 December 2007
Posted 20 December 2007
  I recommend the Primary Papers

In their recent paper Lodge and Grace elegantly demonstrate that hyperactivity of the ventral hippocampus underlies the elevated number of spontaneously active ventral tegmental dopamine neurons, and the concomitant increase in amphetamine-induced locomotor activity, found in MAM-treated rats. Since neonatal MAM treatment recapitulates some of the neurochemical, anatomical, and behavioral abnormalities associated with schizophrenia, these findings raise the possibility that the abnormal subcortical dopamine function associated with this disorder might also result from hippocampal dysfunction.

These findings are consistent with a wealth of evidence suggesting that the hippocampus is a prominent site of dysfunction in the schizophrenic brain (reviewed in Harrison, 2004), and it will be exciting to see the results of the clinical studies described by Anissa Abi-Dargham above.

In the future, it will be important to try to integrate these findings with other models aiming to explain the subcortical dopaminergic hyperactivity seen in schizophrenia. One well-known hypothesis is that these abnormalities might result from hypofunction of the prefrontal cortex (PFC; Weinberger, 1987; Bertolino et al., 2000). Animal studies demonstrate that PFC activity impacts on striatal dopamine function (e.g., Shim et al., 1996) and vice versa (Kellendonk et al., 2006). Thus, it will be of interest to assess the relative contributions of hippocampal and prefrontal dysfunction to these subcortical abnormalities in schizophrenia. Such investigations will necessarily involve the use of both patient populations and appropriate animal model systems. A difficult question will be to establish whether any one of these three regions represents a site of a primary “lesion” in schizophrenia or, perhaps more likely, whether their dysfunction reflects abnormalities in the circuits that link them.

References:

Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology. 2000 Feb;22(2):125-32. Abstract

Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl). 2004 Jun;174(1):151-62. Epub 2004 Mar 6. Review. Abstract

Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 2006 Feb 16;49(4):603-15. Abstract

Shim SS, Bunney BS, Shi WX. Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons. Neuropsychopharmacology. 1996 Nov;15(5):437-41. Abstract

Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987 Jul;44(7):660-9. Abstract

View all comments by Elizabeth Tunbridge