Biomedical subjects

Patricia S Goldman-Rakic

Publications and source records attributed to Patricia S Goldman-Rakic.

35 records · Page 2Linked to original sources

PubMed2003

Amphetamine sensitization of hallucinatory-like behaviors is dependent on prefrontal cortex in nonhuman primates.

BACKGROUND: Repeated amphetamine (AMPH) exposure in nonhuman primates produces a chronic state of monoamine dysregulation and long-lasting changes in behaviors elicited by acute AMPH (including tracking, grasping "at thin air," manipulating nonapparent stimuli, and hypervigilance) in a manner that bears a marked resemblance to symptoms of both amphetamine psychosis and paranoid schizophrenia. These abnormal responses have historically been referred to as psychotomimetic or hallucinatory-like. In contrast to negative symptoms and cognitive deficits, the positive symptoms of schizophrenia including hallucinations have not traditionally been linked to prefrontal dysfunction. METHODS: The dorsomedial (9/8B), dorsolateral (46/8A), and inferior (45/12) sectors of prefrontal cortex were lesioned, singly or in combination. Lesioned and nonlesioned control monkeys were sensitized over a 6-week period using an intermittent schedule of escalating low doses of AMPH. Behavioral responses to acute AMPH after chronic exposure were compared with preexposure responses. RESULTS: Bilateral lesions of prefrontal cortex performed before subchronic AMPH suppressed the sensitization of hallucinatory-like behaviors but markedly enhanced locomotor sensitization compared with control animals. CONCLUSION: These findings indicate that the primate prefrontal cortex may be a substrate for the development of the full complement of behaviors elicited by AMPH sensitization, including hallucinatory-like behaviors.

Amphetamine↗

PubMed2003

Temporally irregular mnemonic persistent activity in prefrontal neurons of monkeys during a delayed response task.

An important question in neuroscience is whether and how temporal patterns and fluctuations in neuronal spike trains contribute to information processing in the cortex. We have addressed this issue in the memory-related circuits of the prefrontal cortex by analyzing spike trains from a database of 229 neurons recorded in the dorsolateral prefrontal cortex of 4 macaque monkeys during the performance of an oculomotor delayed-response task. For each task epoch, we have estimated their power spectrum together with interspike interval histograms and autocorrelograms. We find that 1). the properties of most (about 60%) neurons approximated the characteristics of a Poisson process. For about 25% of cells, with characteristics typical of interneurons, the power spectrum showed a trough at low frequencies (<20 Hz) and the autocorrelogram a dip near zero time lag. About 15% of neurons had a peak at <20 Hz in the power spectrum, associated with the burstiness of the spike train; 2). a small but significant task dependency of spike-train temporal structure: delay responses to preferred locations were characterized not only by elevated firing, but also by suppressed power at low (<20 Hz) frequencies; and 3). the variability of interspike intervals is typically higher during the mnemonic delay period than during the fixation period, regardless of the remembered cue. The high irregularity of neural persistent activity during the delay period is likely to be a characteristic signature of recurrent prefrontal network dynamics underlying working memory.

Action Potentials↗

PubMed2003

Dopamine modulation of perisomatic and peridendritic inhibition in prefrontal cortex.

The computations underlying cognitive functions are performed by a diversity of interactions between interneurons and pyramidal neurons that are subject to modulatory influences. Here we have used paired whole-cell recording to study the influence of dopamine on local inhibitory circuits involving fast-spiking (FS) and non-FS cells, respectively. We found that dopamine depressed inhibitory transmission between FS interneurons and pyramidal neurons but enhanced inhibition between non-FS interneurons and pyramidal cells. FS inhibitory transmission exhibited properties associated with presynaptic action at D(1) receptors that were not evident in non-FS inhibitory connections. In addition, FS and non-FS interneurons differed morphologically, forming contacts on the perisomatic and peridendritic domains, respectively, of their pyramidal cell targets. These findings provide evidence for both a dual mode of inhibition in prefrontal circuitry and circuit-dependent modulation by dopamine.

Action Potentials↗

PubMed2003

Selective modulation of excitatory and inhibitory microcircuits by dopamine.

Dopamine plays an important role in the working memory functions of the prefrontal cortex, functions that are impacted in age-related memory decline, drug abuse, and a wide variety of disorders, including schizophrenia and Parkinson's disease. We have previously reported that dopamine depresses excitatory transmission between pyramidal neurons in the prefrontal cortex. Here, using paired recordings, we have investigated dopaminergic modulation of excitatory transmission from pyramidal neurons to fast-spiking (FS) interneurons. In contrast to its effect on recurrent excitation, dopamine was without effect on excitatory transmission to FS interneurons. However, dopamine has directly enhanced the excitability of the FS interneurons to the extent that even a single excitatory postsynaptic potential could initiate spiking with great temporal precision in some of them. These results indicate that dopamine's effects on excitatory transmission are target-specific and that the axon terminals of pyramidal neurons can be selectively regulated at the level of individual synapses. Thus, dopamine's net inhibitory effect on cortical function is remarkably constrained by the nature of the microcircuit elements on which it acts.

Animals↗

PubMed2003

Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9.

BACKGROUND: Numerous recent studies of postmortem schizophrenic brains have reported the presence of structural abnormalities in the dorsolateral prefrontal cortex (dlPFC) that are consistent with a reduction of neuropil. Ventrolateral prefrontal areas have been studied less extensively, and therefore it is not clear whether these cortices exhibit pathologic abnormalities of the same type and magnitude. Because thought disturbances in schizophrenic patients involve language processing, we have performed a morphometric analysis of Broca's area in the ventral frontal lobe. METHODS: Neuronal and glial density and somal size were assessed via stereologic cell counting in postmortem samples of Broca's area 44 in 9 schizophrenic patients and 14 normal controls. Cell density was reexamined in dorsolateral prefrontal area 9 as an internal control. RESULTS: We did not detect abnormalities in overall or laminar neuronal density, glial density, cortical thickness, or somal size in area 44 of schizophrenic patients. In contrast, neuronal density in area 9 exhibited a 12% increase in the schizophrenic cohort, replicating previous findings. In addition, there was a significant effect of disease on laminar neuronal density in area 9, with neuronal density tending to be higher (7%-29%) in all layers. CONCLUSIONS: The absence of significant cytoarchitectonic abnormalities in Broca's area in the same brains in which the dlPFC exhibited an increase in neuronal density suggests that the neuropil deficit is a regionally specific pathologic finding in schizophrenia and indicates that the dlPFC is a particularly vulnerable target of the disease process.

Adult↗

PubMed2003

Up-regulation of the D1 dopamine receptor-interacting protein, calcyon, in patients with schizophrenia.

BACKGROUND: The dopamine hypothesis remains a prominent influence on research into the pathogenesis of schizophrenia, yet the presence of consistent schizophrenia-linked abnormalities in the presynaptic components of the dopamine system or in dopamine receptors still remains a matter of debate. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenia. Specifically, we examined whether the D1 dopamine receptor-interacting protein calcyon and the D2 dopamine receptor-interacting proteins filamin-A and spinophilin are affected in the dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: Slot blots of dorsolateral prefrontal cortical tissue were used to compare the levels of the 3 proteins of interest in control, schizophrenic, bipolar, and major depression groups (n = 15 per group). The nonschizophrenic psychiatric groups were included to determine the specificity of the detected abnormalities. RESULTS: The dorsolateral prefrontal cortex in schizophrenic patients displayed nearly twice the normal levels of calcyon, whereas filamin-A and spinophilin levels were unaltered. Patients with bipolar disorder or major depression showed no changes in all 3 proteins examined. CONCLUSION: Our findings provide the first evidence that abnormalities in the dopamine system of patients with schizophrenia may lie in altered levels of dopamine receptor-interacting proteins.

Animals↗

PubMed2003

Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling.

Abnormal activity of the dopamine system has been implicated in several psychiatric and neurological illnesses; however, lack of knowledge about the precise sites of dopamine dysfunction has compromised our ability to improve the efficacy and safety of dopamine-related drugs used in treatment modalities. Recent work suggests that dopamine transmission is regulated via the concerted efforts of a cohort of cytoskeletal, adaptor and signaling proteins called dopamine receptor-interacting proteins (DRIPs). The discovery that two DRIPs, calcyon and neuronal Ca(2+) sensor 1 (NCS-1), are upregulated in schizophrenia highlights the possibility that altered protein interactions and defects in Ca(2+) homeostasis might contribute to abnormalities in the brain dopamine system in neuropsychiatric diseases.

Animals↗

PubMed2003

Dissociation of spatial-, object-, and sound-coding neurons in the mediodorsal nucleus of the primate thalamus.

The mediodorsal nucleus (MD) is the thalamic gateway to the prefrontal cortex, an area of the brain associated with spatial and object working memory functions. We have recorded single-neuron activities from the MD nucleus in monkeys trained to perform spatial tasks with peripheral visual stimuli and a nonspatial task with foveally presented pictures of objects and faces-tasks identical to those we have previously used to map regional specializations in the dorso- and ventro-lateral prefrontal cortex, respectively. We found that MD neurons exhibited categorical specificity-either responding selectively to locations in the spatial tasks or preferentially to specific representations of faces and objects in the nonspatial task. Spatially tuned neurons were located in parts of the MD connected with the dorsolateral prefrontal cortex while neurons responding to the identity of stimuli mainly occupied more ventral positions in the nucleus that has its connections with the inferior prefrontal convexity. Neuronal responses to auditory stimuli were also examined, and vocalization sensitive neurons were found in more posterior portions of the MD. We conclude that MD neurons are dissociable by their spatial and nonspatial coding properties in line with their cortical connections and that the principle of information segregation in cortico-cortical pathways extends to the "association" nuclei of the thalamus.

Acoustic Stimulation↗

PubMed2002

Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients.

The delineation of dopamine dysfunction in the mentally ill has been a long-standing quest of biological psychiatry. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients. We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar cases from the Stanley Foundation Neuropathology Consortium display significantly elevated levels of the D2 dopamine receptor desensitization regulatory protein, neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol consumption, or antipsychotic and mood stabilizing medications. The present study supports the hypothesis that schizophrenia and bipolar disorder may be associated with abnormalities in dopamine receptor-interacting proteins.

Alcohol Drinking↗

PubMed2002

Craniofacial dysmorphogenesis in fetally irradiated nonhuman primates: implications for the neurodevelopmental hypothesis of schizophrenia.

BACKGROUND: Craniofacial abnormalities arising from gestational disturbances have been documented in some schizophrenic patients. Reduction of thalamic neurons, a key feature of the neuropathology of schizophrenia, could also have a prenatal origin via disruption of thalamic neurogenesis. This study investigates whether craniofacial dysmorphology and thalamic neuron loss might be associated manifestations of a disruption in embryonic development. METHODS: Thalamic neurons were deleted by exposing fetal macaques to x-rays during thalamic genesis (E33-42). Another group of macaques was irradiated after thalamic genesis (E70-81). Body, head, and facial measurements were obtained from the early irradiated (EX), late irradiated (LX), and control animals at adulthood. RESULTS: Head width, distance between outer eye edges, and ear width were smaller in EX macaques compared with control animals. The LX macaques exhibited only reduced ear width compared with control animals. CONCLUSIONS: These findings indicate that certain features of thalamic neuropathology and craniofacial dysmorphogenesis observed in schizophrenic patients may have a common etiology.

Animals↗

PubMed2002

Abnormalities of thalamic volume and shape detected in fetally irradiated rhesus monkeys with high dimensional brain mapping.

BACKGROUND: Prior research has indicated neuroanatomical abnormalities of the thalamus in schizophrenia. To study the possible pathogenesis, an animal model of neurodevelopmental thalamic damage has been developed by applying low-dose radiation to rhesus monkeys in early gestation. Irradiated monkeys sacrificed as infants demonstrate neuronal losses in specific thalamic nuclei and decreases in cortical neuropil. METHODS: Magnetic resonance scans were collected in adult Rhesus monkeys exposed to irradiation during thalamic neurogenesis (E33-42), after thalamic neurogenesis (E70-81), and in nonirradiated control animals. High dimensional brain mapping was used to compare thalamic volumes and shape characteristics in the three groups of animals. RESULTS: Animals exposed to irradiation at E33-42 showed a significant bilateral loss of thalamic volumes (> 20%) compared with controls and with animals irradiated at E70-81 when total brain volume was used as a covariate in the analysis. Thalamic volume loss was associated with a nonuniform deformation of thalamic shape. CONCLUSIONS: A first-trimester, neurodevelopmental insult in the nonhuman primate during thalamic neurogenesis produces a complex pattern of thalamic volume loss and shape deformation in adulthood. Low-dose irradiation of the fetal primate may be useful for modeling key features of the pathology described in schizophrenic patients.

Animals↗

PubMed2002

The physiological role of 5-HT2A receptors in working memory.

Dorsolateral prefrontal cortex has an essential role in the cognitive process of working memory, dysfunction of which is considered to be a core deficit in schizophrenia. Although this cortical region is densely innervated with 5-HT2A receptors to which atypical antipsychotic drugs bind with high affinity, little is known of the influence of this serotonin receptor subtype on prefrontal function. We addressed this issue by examining the effects of iontophoresis of selective receptor ligands on prefrontal neurons possessing spatially tuned delay activity, or "memory fields," in monkeys performing a delayed-response task. Memory fields of putative pyramidal cells were attenuated by iontophoresis of 5-HT2A antagonists, which primarily produced a reduction in delay activity for preferred target locations. Conversely, 5-HT2A stimulation by alpha-methyl-5-HT or 5-HT itself, accentuated the spatial tuning of these neurons by producing a modest increase in activity for preferred target locations and/or a reduction in activity for nonpreferred locations. The agonist effects could be reversed by the selective antagonist MDL100,907, and were dose-dependent, such that high levels attenuated spatial tuning by profoundly reducing delay activity. A role for feedforward inhibitory circuitry in these effects was supported by the finding that 5-HT2A blockade also attenuated the memory fields of putative interneurons. We conclude that prefrontal 5-HT2A receptors have a hitherto unrecognized role in the cognitive function of working memory, which involves actions at both excitatory and inhibitory elements within local circuitry.

Action Potentials↗

PubMed2002

The "psychic cell" of Ramón y Cajal.

Santiago Ramón y Cajal might have envisioned, but likely could not have anticipated, the scientific advances that have allowed the functional validation of the existence of a "psychic cell" in the prefrontal cortex and its extension to human cognition at the end of the 20th century. This achievement rests not only on the shoulders of giants but on many small steps in the development of primate cognition, single and multiple unit recording in behaving monkeys, light and electron microscopic analysis of cortical circuitry no less than on the evolution of concepts about memory systems and parallel processing networks, among other advances. We can only wonder what the next generation of neuroscientists will bring to our understanding of brain-behavior relationships and human information capacity.

Action Potentials↗

PubMed2002

An auditory domain in primate prefrontal cortex.

Although neuroimaging studies confirm the frontal lobe's involvement in language processes and auditory working memory, the cellular and network basis of these functions is unclear. Physiological studies of the frontal lobe in non-human primates have focused on visual working memory and auditory spatial processing in dorsolateral prefrontal cortex (PFC), although the candidate PFC areas for non-spatial acoustic processing lie in the ventrolateral PFC (areas 12 and 45), which receives afferents from physiologically and anatomically defined auditory cortex. We recorded neuronal responses from ventrolateral PFC to auditory cues in awake monkeys under controlled conditions and report that the macaque ventrolateral PFC contains an auditory responsive domain in which neurons show responses to complex sounds, including animal and human vocalizations.

Acoustic Stimulation↗

PubMed2002

A role for inhibition in shaping the temporal flow of information in prefrontal cortex.

The prefrontal cortex is important in guiding or inhibiting future responses, which requires the temporal integration of events and which provides continuity to the thought process. No cellular mechanism has been proposed to explain how the mental representation of a response or idea is linked to the next. Using simultaneous recordings in monkeys, we revealed inhibitory interactions between neurons active at different time points relative to the cue presentation, delay interval and response period of a working memory task. These findings suggest an important role of inhibition in the cerebral cortex-controlling the timing of neuronal activities during cognitive operations and thereby shaping the temporal flow of information.

Animals↗

PubMed2002

Correlated discharges among putative pyramidal neurons and interneurons in the primate prefrontal cortex.

Neurophysiological recordings have revealed that the discharges of nearby cortical cells are positively correlated in time scales that range from millisecond synchronization of action potentials to much slower firing rate co-variations, evident in rates averaged over hundreds of milliseconds. The presence of correlated firing can offer insights into the patterns of connectivity between neurons; however, few models of population coding have taken account of the neuronal diversity present in cerebral cortex, notably a distinction between inhibitory and excitatory cells. We addressed this question in the monkey dorsolateral prefrontal cortex by recording neuronal activity from multiple micro-electrodes, typically spaced 0.2-0.3 mm apart. Putative excitatory and inhibitory neurons were distinguished based on their action potential waveform and baseline discharge rate. We tested each pair of simultaneously recorded neurons for presence of significant cross-correlation peaks and measured the correlation of their averaged firing rates in successive trials. When observed, cross-correlation peaks were centered at time 0, indicating synchronous firing consistent with two neurons receiving common input. Discharges in pairs of putative inhibitory interneurons were found to be significantly more strongly correlated than in pairs of putative excitatory cells. The degree of correlated firing was also higher for neurons with similar spatial receptive fields and neurons active in the same epochs of the behavioral task. These factors were important in predicting the strength of both short time scale (<5 ms) correlations and of trial-to-trial discharge rate covariations. Correlated firing was only marginally accounted for by motor and behavioral variations between trials. Our findings suggest that nearby inhibitory neurons are more tightly synchronized than excitatory ones and account for much of the correlated discharges commonly observed in undifferentiated cortical networks. In contrast, the discharge of pyramidal neurons, the sole projection cells of the cerebral cortex, appears largely independent, suggesting that correlated firing may be a property confined within local circuits and only to a lesser degree propagated to distant cortical areas and modules.

Animals↗

PubMed2002

Smaller frontal gray matter volume in postmortem schizophrenic brains.

OBJECTIVE: The prefrontal cortex exhibits prominent functional, biochemical, and anatomic abnormalities in schizophrenic patients. However, smaller than normal volume of the frontal lobe has not been found in previous postmortem studies of schizophrenic subjects, and magnetic resonance imaging (MRI) scans of schizophrenic subjects have not consistently revealed frontal volumetric deficits. The variability in MRI findings may be related partly to difficulty in defining the posterior border of the frontal lobe. In this study, precise measurements of frontal lobe volume from postmortem brains were derived by defining the posterior border according to the brain atlas of Talairach and Tournoux and by applying stereologic methods to estimate gray and white matter volumes. METHOD: Whole, or nearly whole, formalin-fixed left hemispheres from 14 schizophrenic and 19 normal comparison subjects were analyzed. Total cortical gray and white matter volumes, as well as frontal cortical gray and white matter volumes, were measured by using the Cavalieri method. RESULTS: Only frontal gray matter volume was significantly smaller in the schizophrenic subjects than in the comparison subjects (12% difference). The differences between groups in total gray and white matter volumes and frontal white matter volume (6%-8% smaller in the schizophrenic subjects than in the comparison subjects) did not reach statistical significance. CONCLUSIONS: The smaller frontal gray matter volume observed in schizophrenic brains suggests that pathology of the frontal lobe may be more severe than that of the three posterior lobes and may account for the prominence of prefrontal dysfunction associated with schizophrenia.

Adult↗