[show abstract][hide abstract] ABSTRACT: Comparing prefrontal cortical activity during particular phases of working memory in healthy subjects and individuals diagnosed with schizophrenia might help to define the phase-specific deficits in cortical function that contribute to cognitive impairments associated with schizophrenia. This study featured a spatial working memory task, similar to that used in nonhuman primates, that was designed to facilitate separating brain activation into encoding, maintenance, and response phases.
Fourteen patients with schizophrenia (4 medication-free) and 12 healthy comparison participants completed functional magnetic resonance imaging while performing a spatial working memory task with two levels of memory load.
Task accuracy was similar in patients and healthy participants. However, patients showed reductions in brain activation during maintenance and response phases but not during the encoding phase. The reduced prefrontal activity during the maintenance phase of working memory was attributed to a greater rate of decay of prefrontal activity over time in patients. Cortical deficits in patients did not appear to be related to antipsychotic treatment. In patients and in healthy subjects, the time-dependent reduction in prefrontal activity during working memory maintenance correlated with poorer performance on the memory task.
Overall, these data highlight that basic research insights into the distinct neurobiologies of the maintenance and response phases of working memory are of potential importance for understanding the neurobiology of cognitive impairment in schizophrenia and advancing its treatment.
[show abstract][hide abstract] ABSTRACT: Recent observations suggest that calcyon, a novel single transmembrane protein implicated in schizophrenia and attention-deficit/hyperactivity disorder, regulates clathrin-mediated endocytosis in brain. To explore the role of calcyon in neurotransmission, we investigated its distribution in the neuropil of the primate prefrontal cortex (PFC), striatum (STR) and mediodorsal thalamic nucleus (MD), three brain regions implicated in these neuropsychiatric disorders. Calcyonimmunoreactivity revealed by immunoperoxidase technique, was localized in both pre- and postsynaptic structures including axons, spines and dendrites, as well as myelinated fibers and astroglial processes in all the three brain regions. The morphological diversity of immunopositive boutons suggest that in addition to glutamatergic, calcyon could regulate GABAergic as well as monoaminergic neurotransmission. Consistent with the role of calcyon in endocytosis, calcyon-immunoreactivity was rarely found at the synaptic membrane specializations proper, although it was present in distal compartments of neuronal processes establishing synapses. Given the widespread upregulation of calcyon in schizophrenic brain, these findings underscore a potential association with deficits in a range of neurotransmitter systems in the cortico-basal ganglia-thalamic loop.
[show abstract][hide abstract] ABSTRACT: Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3(1/2) years postsensitization, sensitized, and AMPH-naïve control monkeys were killed. Blocks of prefrontal cortex were Golgi-impregnated for elucidation of pyramidal dendritic morphology in layers II/superficial III (II/IIIs), deep III, and V/VI. In AMPH-sensitized animals as compared to AMPH-naïve controls, pyramidal dendrites in layer II/IIIs exhibited reduced overall dendritic branching and reduced peak spine density (22%) on the apical trunk. Across all layers, the distance from soma to peak spine density along the apical trunk was decreased (126.38+/-7.65 mum in AMPH-sensitized compared to 162.98+/-7.26 microm in AMPH-naïve controls), and basilar dendritic length was reduced (32%). These findings indicate that chronic dopamine dysregulation, consequent to AMPH sensitization, results in enduring, atrophic changes in prefrontal pyramidal dendrites that resemble the pathologic alterations described in patients with schizophrenia and may contribute to the persistence of schizophrenia-like behavioral changes and cognitive dysfunction associated with sensitization. These findings may also provide key insights into the etiologic origin of the pronounced behavioral disturbances and cognitive dysfunction associated with schizophrenia.
[show abstract][hide abstract] ABSTRACT: The regulation of cognitive activity relies on the flexibility of prefrontal cortex functions. To study this mechanism we compared monkey dorsolateral prefrontal activity in two different spatial cognitive tasks: a delayed response task and a self-organized problem-solving task. The latter included two periods, a search by trial and error for a correct response, and a repetition of the response once discovered. We show that (1) delay activity involved in the delayed task also participates in self-generated responses during the problem-solving task and keeps the same location preference, and (2) the amplitude of firing and the strength of spatial selectivity vary with task requirement, even within search periods while approaching the correct response. This variation is dissociated from pure reward probability, but may have a link with uncertainty because the selectivity dropped when reward predictability was maximal. Overall, we show that spatially tuned delay activity of prefrontal neurons reflects the varying level of engagement in control between different spatial cognitive tasks and during self-organized behavior.
Journal of Neuroscience 12/2006; 26(44):11313-23. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Much of our knowledge on trafficking of neurotransmitter receptors derives from heterologous expression systems and neurons in vitro. Understanding these dynamics in vivo for dopamine receptors, and D2 receptors (D2Rs) in particular, presents a foremost challenge as their pharmacological manipulation underlies antipsychotic medications and drug abuse, which may in turn alter response to endogenous dopamine. Here we present the first ultrastructural evidence of clathrin-mediated endocytosis of D2Rs or any other neurotransmitter receptor in the primate brain. We have captured in situ the insertion of D2Rs in clathrin-coated membrane pits, resulting in receptor sorting in primary endosomes. Endocytosis was specific to nonsynaptic membranes of distal dendrites, and virtually absent from larger shafts, spines, axons and perikarya expressing D2Rs. The selective association of D2Rs with the clathrin endocytotic pathway of high-order dendrites identifies a novel substrate for monitoring and adjusting dopaminoception, as well as a potent target for dysregulation, and manipulation, of D2R signalling in mental illness.
European Journal of Neuroscience 10/2006; 24(5):1395-403. · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: The prefrontal cortex is specially adapted to generate persistent activity that outlasts stimuli and is resistant to distractors, presumed to be the basis of working memory. The pyramidal network that supports this activity is unknown. Multineuron patch-clamp recordings in the ferret medial prefrontal cortex showed a heterogeneity of synapses interconnecting distinct subnetworks of different pyramidal cells. One subnetwork was similar to the pyramidal network commonly found in primary sensory areas, consisting of accommodating pyramidal cells interconnected with depressing synapses. The other subnetwork contained complex pyramidal cells with dual apical dendrites displaying nonaccommodating discharge patterns; these cells were hyper-reciprocally connected with facilitating synapses displaying pronounced synaptic augmentation and post-tetanic potentiation. These cellular, synaptic and network properties could amplify recurrent interactions between pyramidal neurons and support persistent activity in the prefrontal cortex.
[show abstract][hide abstract] ABSTRACT: Neuroimaging of the human brain has opened the way for a genuine understanding of human cognition; but the circuitry and cellular
basis of the extraordinary information processing capacity of humans can be addressed only in experimental animals such as
nonhuman primates by using the 2-DG autoradiographic method. This method requires sacrifice of the animal and sectioning of
the brain into serial sections followed by production of autoradiographs of individual brain sections which are not in register.
We have developed a new automated alignment method to reconstitute the autoradiographs. Our alignment method automatically
finds the 2-D spatial mapping and the homologies between the slices and robustly accounts for the natural and artifactual
differences by applying the powerful mechanism of outlier rejection adapted from the robust statistics literature.
[show abstract][hide abstract] ABSTRACT: Various normal and pathological forms of synchronized population activity are generated by recurrent excitation among pyramidal neurons in the neocortex. However, the intracellular signaling mechanisms underlying this activity remain poorly understood. In this study, we have examined the cellular properties of synchronized epileptiform activity in the prefrontal cortex with particular emphasis on a potential role of intracellular calcium stores. We find that the zero-magnesium-induced synchronized activity is blocked by inhibition of sarco-endoplasmic reticulum Ca(2+)-ATPases, phospholipase C (PLC), the inositol 1,4,5-trisphosphate (IP3) receptor, and the ryanodine receptor. This same activity is, however, not affected by application of metabotropic glutamatergic receptor (mGluR) agonists, nor by introduction of an mGluR antagonist. These results suggest that persistent synchronized activity in vitro is dependent upon calcium release from internal calcium stores through the activation of PLC-IP3 receptor pathway. Our findings also raise the possibility that intracellular calcium release may be involved in the generation of pathologic synchronized activity in epilepsy in vivo and in physiological forms of synchronized cortical activity.
[show abstract][hide abstract] ABSTRACT: Neuroimaging studies commonly show widespread activations in the prefrontal cortex during various forms of working memory and long-term memory tasks. However, the anterior prefrontal cortex (aPFC, Brodmann area 10) has been mainly associated with retrieval in episodic memory, and its role in working memory is less clear. We conducted an event-related functional magnetic resonance imaging study to examine brain activations in relation to recognition in a spatial delayed-recognition task. Similar to the results from previous findings, several frontal areas were strongly activated during the recognition phase of the task, including the aPFC, the lateral PFC and the anterior cingulate cortex. Although the aPFC was more active during the recognition phase, it was also active during the delay phase of the spatial working memory task. In addition, the aPFC showed greater activity in response to negative probes (non-targets) than to positive probes (targets). While our analyses focused on examining signal changes in the aPFC, other prefrontal regions showed similar effects and none of the areas were more active in response to the positive probes than to the negative probes. Our findings support the conclusion that the aPFC is involved in working memory and particularly in processes that distinguish target and non-target stimuli during recognition.
[show abstract][hide abstract] ABSTRACT: Structures of the cerebral cortex expressing the D2 dopamine receptor subtype (D2) are important sites of action of antipsychotic drugs. It has also been repeatedly suggested that the prefrontal cortex plays a significant role in neuropsychiatric disorders, including schizophrenia. Here, by using single and double immunohistochemical techniques with electron microscopy, we investigated in the primate prefrontal cortex the ultrastructural localization of D2 and we compared it with that of the neuronal calcium sensor-1 (NCS-1), a neuron-specific calcium-binding and D2-interacting protein. D2 immunoreactivity, revealed with preembedding immunoperoxidase in single labeling and with preembedding immunogold for double labeling, was localized in cell bodies with ultrastructural characteristics of both neurons and astroglia. D2 was localized in pre- and postsynaptic structures, including spines and dendrites, and in both excitatory- and inhibitory-like axon terminals. Immunogold labeling revealed peri- and extrasynaptic localization of D2 in postsynaptic structures, whereas extrasynaptic labeling was typically found in boutons. NSC-1 immunoreactivity was abundant in pre- and postsynaptic structures, in which it was also colocalized with D2. With the present strategy (that has high resolution but relatively limited sensitivity), NSC-1 was observed in about 10% of the D2-immunopositive spines and in a lower proportion of D2-immunopositive dendrites and boutons. The data demonstrate the localization of D2 in pre- and postsynaptic as well as extra- and perisynaptic structures of the primate prefrontal cortex. The data also show the coexistence of NCS-1 and D2 at the ultrastructural level. The latter finding suggests a role for NCS-1 in desensitization of D2 in the prefrontal cortex.
The Journal of Comparative Neurology 09/2005; 488(4):464-75. · 3.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: The main thalamic afferentation of the prefrontal cortex (PFC) originates in the mediodorsal nucleus (MD). Although it is suggested that this pathway is affected in schizophrenia, there is a lack of functional and structural data regarding its synaptic organization. The scope of this study was to characterize the ultrastructural features of thalamocortical synapses formed by afferents from the MD by applying anterograde tract tracing, immunohistochemical detection of parvalbumin (PV, a probable marker of thalamocortical endings), and quantitative electron microscopic techniques to the PFC of the macaque monkey. Our findings indicate that anterogradely-labeled and PV-immunoreactive boutons exhibit similar ultrastructural properties, characterized by their larger size, higher incidence of release sites and a higher occurrence of mitochondria when compared to non-labeled, excitatory-like endings in the middle layers of the PFC. Although most of the contacts were made on spines in both cases, PV-immunopositive axon terminals apparently targeted dendritic shafts at about twice the frequency found for anterogradely-labeled afferents from the MD (20.5% and 9.5%, respectively). This result suggests diversity among thalamocortical and/or PV-immunoreactive axon terminals of the PFC. In accordance with studies in other cortical areas, our findings suggest that corollary discharge through the mediodorsal thalamocortical projection is also adapted to synaptic transmission with high efficacy and probably exhibits marked short-term temporal dynamics in the PFC.
Experimental Brain Research 08/2005; 164(2):148-54. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Amphetamine (AMPH) sensitization in monkeys produces long-lasting behavioral changes that model positive (hallucinatory-like behaviors) and negative (psychomotor depression) symptoms of schizophrenia. The extent to which this model produces the core deficit in schizophrenia--working memory impairment--is unknown.
Two groups of rhesus monkeys were sensitized to AMPH over 6 weeks. In one group, acquisition of cognitive tasks (delayed response, visual discrimination, delayed nonmatch-to-sample) was examined beginning 6+ months postsensitization. The second group was pretrained to stability on delayed response before sensitization. Regional postmortem concentrations of dopamine and its metabolites were examined in tissue from age-matched AMPH-naive and AMPH-sensitized monkeys using high-performance liquid chromatography with electrochemical detection (HPLC-ECD).
The AMPH-sensitized monkeys were profoundly impaired in their ability to acquire cognitive tasks compared with AMPH-naïve monkeys. Pretrained monkeys showed impaired delayed response performance for several months following sensitization. Analysis by HPLC revealed that AMPH sensitization significantly reduced dopamine turnover in prefrontal cortex and striatum.
Impairments in the acquisition and performance of spatial delayed response in association with reduced dopamine turnover in prefrontal cortex following AMPH sensitization provide further support for the relevance of this model to both the etiology and the treatment of cognitive dysfunction in schizophrenia.
[show abstract][hide abstract] ABSTRACT: Dopaminergic modulation of glutamate neurotransmission in prefrontal cortex (PFC) microcircuits is commonly perceived as a basis for cognitive operations. Yet it appears that although the control of recurrent excitation between deep-layer prefrontal pyramids may involve presynaptic and postsynaptic D1 receptor (D1R) mechanisms, pyramid-to-interneuron communication will engage a postsynaptic D1R component. The substrate underlying such target-specific neuromodulatory patterns was investigated in the infragranular PFC with immunoelectron microscopy for D1R and parvalbumin, a marker for fast-spiking interneurons. In addition to their proverbial postsynaptic expression, gold-labeled D1Rs were distinctly distributed on perisynaptic/extrasynaptic membranes and the axoplasm of 13% of excitatory-like, presumably glutamatergic varicosities. Most importantly, presynaptic D1Rs were highly specific with regard to the cellular compartment and neurochemical identity of the postsynaptic neuron, being present in spine-targeting varicosities but distinctly absent from those synapsing with parvalbumin profiles often coexpressing D1Rs. We define therein an axonal D1 heteroreceptor component, apparently mediating volume neurotransmission, yet strategically positioned to convey target cell-specific modulation of the glutamatergic drive. We also indicate that presynaptic D1R mechanisms may indeed be associated with recurrent excitation in prefrontal microcircuits, consistent with physiological evidence for a role of these receptors in modulating the persistent activity-profile of neurons essential for working memory.
Journal of Neuroscience 03/2005; 25(5):1260-7. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Schizophrenia is associated with reductions in thalamic neuronal number and cortical gray matter volume. Exposure of nonhuman primates to x-irradiation in early gestation has previously been shown to decrease thalamic volume and neuronal number. Here we examine whether early gestational irradiation also results in cortical volume reduction.
High-resolution, T1-weighted magnetic resonance scans were collected in adult monkeys 1) exposed to irradiation during the early gestational period (E33-E42) corresponding to thalamic neurogenesis, 2) irradiated in midgestation (E70-81) during neocortical neurogenesis, and 3) not exposed to irradiation. Cortical gray matter and white matter volumes were derived via manual segmentation; frontal and nonfrontal volumes were distinguished via sulcal landmarks.
Monkeys irradiated in early gestation exhibited a trend reduction in nonfrontal gray matter volume (17%) and significant reductions in white matter volume in frontal (26%) and nonfrontal (36%) lobes. Monkeys irradiated in midgestation had smaller gray (frontal: 28%; nonfrontal: 22%) and white matter (frontal: 29%; nonfrontal: 38%) volumes.
The cortical deficits observed in midgestationally irradiated monkeys are consistent with a reduction in cortical neuronal number. Cortical volume reductions following early gestational irradiation may be secondary to reduced thalamic neuronal number and therefore model the thalamocortical pathology of schizophrenia.
[show abstract][hide abstract] ABSTRACT: We previously reported that neurons in the mediodorsal thalamic nucleus (MD) are topographically organized and express spatial and nonspatial coding properties similar to those of the prefrontal areas with which they are connected. In the course of mapping the dorsal thalamus, we also studied neurons in a subset of thalamic nuclei (the caudal part of the ventral lateral nucleus (VLc), the oral part of the ventral posterior lateral nucleus (VPLo), the parvocellular part of the ventral anterior nucleus (VApc)) lateral to the MD and just across the internal medullary lamina. We compared these "paralaminar" neurons to MD neurons by having monkeys perform the same spatial and nonspatial cognitive tasks as those used to investigate the MD; these included two saccadic tasks-one requiring delayed and the other immediate responses-and one picture fixation task. Of the paralaminar thalamic neurons modulated by the saccadic tasks, a majority had saccade-related activity, and this was nearly always spatially tuned. Also, for about half of these neurons, the saccade-related activity occurred exclusively during the delayed-response task. No neurons with event-related activity in the saccadic tasks were preferentially modulated by specific picture stimuli, although other neurons were. All of these results were similar to what we had found for MD neurons. However, in contrast to the high proportion of presaccadic responses observed in the MD, the majority of saccade-related neurons in paralaminar thalamus exhibited mid- or postsaccadic activity, i.e., that started during or after the saccade. Our findings suggest that neurons in the paralaminar thalamus may be possible conduits of oculomotor feedback signals, especially during memory-guided saccades.
Journal of Neurophysiology 02/2005; 93(1):614-9. · 3.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: The common preconception about central nervous system neurones is that thousands of small postsynaptic potentials sum across the entire dendritic tree to generate substantial firing rates, previously observed in in vivo experiments. We present evidence that local inputs confined to a single basal dendrite can profoundly influence the neuronal output of layer V pyramidal neurones in the rat prefrontal cortical slices. In our experiments, brief glutamatergic stimulation delivered in a restricted part of the basilar dendritic tree invariably produced sustained plateau depolarizations of the cell body, accompanied by bursts of action potentials. Because of their small diameters, basolateral dendrites are not routinely accessible for glass electrode measurements, and very little is known about their electrical properties and their role in information processing. Voltage-sensitive dye recordings were used to follow membrane potential transients in distal segments of basal branches during sub- and suprathreshold glutamate and synaptic stimulations. Recordings were obtained simultaneously from multiple dendrites and multiple points along individual dendrites, thus showing in a direct way how regenerative potentials initiate at the postsynaptic site and propagate decrementally toward the cell body. The glutamate-evoked dendritic plateau depolarizations described here are likely to occur in conjunction with strong excitatory drive during so-called 'UP states', previously observed in in vivo recordings from mammalian cortices.
The Journal of Physiology 08/2004; 558(Pt 1):193-211. · 4.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: The explicit yet enigmatic involvement of dopamine in cortical physiology is in part volumetric (beyond the synapse), as is apparently the action of neuroleptics targeting dopamine receptors. The notion that nonsynaptic neuronal membranes would translate extracellular dopamine into receptor-specific spatiotemporal downstream signaling, similar to the chemical synapse, is intriguing. Here, we report that dopamine D5 (but not D1 or D2) receptors in the perisomatic plasma membrane of prefrontal cortical neurons form discrete and exclusively extrasynaptic microdomains with inositol 1,4,5-trisphosphate-gated calcium stores of subsurface cisterns and mitochondria. These findings introduce a novel dopaminoceptive substratum in the brain and a unique D5 receptor-specific signaling paradigm.
Journal of Neuroscience 07/2004; 24(23):5292-300. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Working memory performance is considered to be a core deficit in schizophrenia and the best predictor of social reintegration and propensity for relapse. This cardinal cognitive process is critical for human reasoning and judgment and depends upon the integrity of prefrontal function. Prefrontal dysfunction in schizophrenia has been linked to altered dopaminergic and glutamatergic transmission. However, to date, antipsychotics provide no substantial relief from the debilitating cognitive consequences of this disease.
This review examines the key rodent and non-human primate models for elucidating the neural mechanisms of working memory and their neuromodulation. We compare the physiology and pharmacology of working memory between the normal state and experimentally induced models of prefrontal dysfunction and evaluate their relevance for schizophrenia.
Rodent models have demonstrated the significance of aberrant dopaminergic and glutamatergic signaling in medial prefrontal cortex for working memory. However, there is some question as to the extent to which rodent tests of working memory tap into the same process that is compromised in schizophrenia. Non-human primates provide an unexcelled model for the study of influences on prefrontal function and working memory due to the high degree of homology between human and non-human primates in the relationship between prefrontal cortex and higher cognitive capacities. Moreover, non-human primate models of prefrontal dysfunction including amphetamine sensitization, subchronic phencyclidine, and neurodevelopmental insult are ideal for the analysis of novel compounds for the treatment of cognitive dysfunction in schizophrenia, thereby facilitating the translation between preclinical drug development and clinical trials.
[show abstract][hide abstract] ABSTRACT: Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D(1) receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D(1) stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia.
This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D(1) signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function.
Dopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D(1) receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D(1) receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia.