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Results for “Prefrontal Cortex”

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PubMed2001

Prefrontal cortex as the site of estrogen's effect on cognition.

The hippocampus has long been presumed the primary site of action of estrogens on cognition; and explicit memory is considered the cognitive function most vulnerable to menopausal loss of estrogen. We hypothesize instead that the prefrontal cortex and its neural circuitry are prime mediators of estrogen's role in cognition. We also propose that previously reported menopausal cognitive decline, presumed to be hippocampally mediated, may be secondary to executive dysfunction. We used a cross sectional design to compare the performance of nine menopausal women on hormone replacement therapy (HRT) and 10 menopausal women with no prior exposure to HRT on a battery of neuropsychological tests. The battery was comprised primarily of tests of memory and executive functioning. Executive functioning is mediated by the frontal lobes and encompasses working memory, directed attention, the inhibition of inappropriate responses, cognitive set switching, and behavioral monitoring. Unlike most previous studies, we used a memory measure that yields multiple scores reflecting various problem-solving strategies and error types, thus isolating spared and impaired cognitive processes. Results yielded both qualitative and quantitative evidence for disruption of cognitive processes subserved by the frontal lobes rather than the hippocampus: 1) despite intact free recall on a list-learning task (CVLT), untreated menopausal women were relatively impaired in correctly recognizing words previously learned and distinguishing them from items not on the list (discriminability), 2) untreated women also had difficulty inhibiting inappropriate responses in the form of perseverative errors, and 3) the non-HRT group consistently performed worse on the N-back test of working memory. The prefrontal cortex is critical for intact working memory and estrogen enhances performance on working memory tasks. In conclusion, this study provides preliminary evidence for executive dysfunction in untreated menopausal women as women with HRT outperformed women without HRT on tests requiring directed attention, inhibition of inappropriate responses, and cognitive set switching.

Cognition↗

PubMed2004

Sex-related developmental differences in the lateralized activation of the prefrontal cortex and amygdala during perception of facial affect.

The lateralization of cognitive abilities is influenced by a number of factors, including handedness, sex, and developmental maturation. To date, a small number of studies have examined sex differences in the lateralization of cognitive and affective functions, and in only few of these have the developmental trajectories of these lateralized differences been mapped from childhood through early adulthood. In the present study, a cross-sectional design was used with healthy children (n=7), adolescents (n= 12), and adults (n= 10) who underwent functional magnetic resonance imaging (fMRI) during a task that required perceiving fearful faces. Males and females differed in the asymmetry of activation of the amygdala and prefrontal cortex across the three age groups. For males, activation within the dorsolateral prefrontal cortex was bilateral in children, right lateralized in adolescents, and bilateral in adults, whereas females showed a monotonic relationship with age, with older females showing more bilateral activation than younger ones. In contrast, amygdala activation was similar for both sexes, with bilateral activation in children, right-lateralized activation in adolescents, and bilateral activation in adults. These results suggest that males and females show different patterns of lateralized cortical and subcortical brain activation across the period of development from childhood through early adulthood.

Affect↗

PubMed2006

Altered neuropeptide processing in prefrontal cortex of Cpe (fat/fat) mice: implications for neuropeptide discovery.

The biosynthesis of most neuropeptides and peptide hormones requires a carboxypeptidase such as carboxypeptidase E, which is inactive in Cpe(fat/fat) mice due to a naturally occurring point mutation. To assess the role of carboxypeptidase E in the processing of peptides in the prefrontal cortex, we used a quantitative peptidomics approach to examine the relative levels of peptides in Cpe(fat/fat) versus wild-type mice. Peptides representing internal fragments of prohormones and other secretory pathway proteins were decreased two- to 10-fold in the Cpe(fat/fat) mouse prefrontal cortex compared with wild-type tissue. Degradation fragments of cytosolic proteins showed no major differences between Cpe(fat/fat) and wild-type mice. Based on this observation, a search strategy for neuropeptides was performed by screening for peptides that decreased in the Cpe(fat/fat) mouse. Altogether, 32 peptides were identified, of which seven have not been previously reported. The novel peptides include fragments of VGF, procholecystokinin and prohormone convertase 2. Interestingly, several of the peptides do not fit with the consensus sites for prohormone convertase 1 and 2, raising the possibility that another endopeptidase is involved with their biosynthesis. Taken together, these findings support the proposal that carboxypeptidase E is the major, but not the only, peptide-processing carboxypeptidase and also demonstrate the feasibility of searching for novel peptides based on their decrease in Cpe(fat/fat) mice.

Amino Acid Sequence↗

PubMed2006

Monkey dorsolateral prefrontal cortex sends task-selective signals directly to the superior colliculus.

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the ability to perform complex behaviors requiring the implementation of cognitive control. A central supposition of models of prefrontal function is that the DLPFC engages control by selectively modulating the activity of target structures to which it is connected, but no studies in the primate have directly investigated DLPFC output signals. Here, we recorded the activity of DLPFC neurons identified as sending a direct projection to the superior colliculus, a midbrain oculomotor structure, while monkeys performed alternating blocks of trials in which they had to look toward a flashed peripheral stimulus (prosaccades) and trials in which they had to look away from the stimulus in the opposite direction (antisaccades). We report the first direct evidence that the primate DLPFC sends task-selective signals to a target structure. This supports the notion that the DLPFC orchestrates the activity of other brain areas in accordance with task requirements.

Action Potentials↗

PubMed1994

Differential effects of locally administered clozapine and haloperidol on dopamine efflux in the rat prefrontal cortex and caudate-putamen.

Previous research has shown that systemically administered antipsychotic drugs enhance dopamine release from the nigrostriatal and mesocortical dopamine pathways. However, the degree of enhancement differs as a function of the drug used (atypical versus typical antipsychotic) and the dopamine pathway examined. The present studies examined whether these differences result from differential actions of these drugs on dopamine terminal regions. Clozapine or haloperidol was infused locally into the caudate-putamen or prefrontal cortex through reverse microdialysis. Although both drugs increased extracellular dopamine levels, clozapine produced greater effects than haloperidol in the prefrontal cortex, whereas haloperidol produced greater effects in the caudate-putamen. These results suggest that neurochemical differences within dopamine terminal regions may explain the differential actions of antipsychotic drugs on striatal and cortical dopamine release.

Animals↗

PubMed2004

Activation of human medial prefrontal cortex during autonomic responses to hypoglycemia.

Studies in humans implicate the medial prefrontal cortex (MPFC) in complex cognitive and emotional states. We measured regional cerebral blood flow (CBF) four times each during euglycemia (5.2 +/- 0.2 mmol/liter) and hypoglycemia (3.0 +/- 0.3 mmol/liter) in nine normal human volunteers. Autonomic responses during hypoglycemia were manifested by increases in neurogenic symptoms, heart rate, and plasma levels of epinephrine, norepinephrine, and pancreatic polypeptide. Typical symptoms of hypoglycemia were mild, and none reflected evidence of cognitive or emotional stress. Quantitative CBF fell 6-8% in the cerebrum, brainstem, and cerebellum. Analysis of regional CBF differences identified neuronal activation during hypoglycemia in bilateral MPFC (areas 24 and 32) and bilateral thalamus. These results provide evidence that the MPFC participates in the autonomic responses to simple physiological stimuli in humans.

Adolescent↗

PubMed1999

Neuronal correlates of parametric working memory in the prefrontal cortex.

Humans and monkeys have similar abilities to discriminate the difference in frequency between two mechanical vibrations applied sequentially to the fingertips. A key component of this sensory task is that the second stimulus is compared with the trace left by the first (base) stimulus, which must involve working memory. Where and how is this trace held in the brain? This question was investigated by recording from single neurons in the prefrontal cortex of monkeys while they performed the somatosensory discrimination task. Here we describe neurons in the inferior convexity of the prefrontal cortex whose discharge rates varied, during the delay period between the two stimuli, as a monotonic function of the base stimulus frequency. We describe this as 'monotonic stimulus encoding', and we suggest that the result may generalize: monotonic stimulus encoding may be the basic representation of one-dimensional sensory stimulus quantities in working memory. Thus we predict that other behavioural tasks that require ordinal comparisons between scalar analogue stimuli would give rise to monotonic responses similar to those reported here.

Animals↗

PubMedDate not supplied

Spatial strategy elaboration in egocentric and allocentric tasks following medial prefrontal cortex lesions in the rat.

We evaluated the role of the medial prefrontal cortex (mPFC) in the elaboration of egocentric navigation strategies in a water maze (WM). Lesions of mPFC cell bodies was achieved in 21 rats using bilateral injections of ibotenic acid (IA); 13 control rats were injected with saline. After 17 days, rats had to learn an allocentric (using external cues: 10 lesioned, 7 saline rats) or an egocentric WM (using internal/kinetic cues: 10 lesioned, 6 saline rats) over six trials in a same session. The initial trajectory on the sixth trial was used as an index of the elaboration of a navigation strategy. In the egocentric test, lesioned rats were more rarely located in the target quadrant than control rats. No differences were found between lesioned and control rats in the allocentric test. These results show that lesions of the mPFC impairs the capacity to elaborate an egocentric navigation strategy.

Animals↗

PubMed1977

A stereotaxic atlas of the prefrontal cortex of the cat.

A survey of existing atlases of the cat's brain has revealed a lack of coronal sections on the levels of the prefrontal cortex. On the other hand, neurophysiological and behavioral studies of this region have increased greatly in recent years. As the extent of coronal sections through the prefrontal cortex was seen to differ markedly even at separations of 1 mm, a stereotaxic atlas was made on the basis of brain sections of 16 mongrel cats. Brains were cut with the use of the paraffin or freezing method, and stained with cresyl violet, Luxol fast blue, or Kluver-Barrera's combination. Statistical methods were used to yield representative coronal outlines of sections from +20 to +30 mm anterior in 1 mm steps. A comparison with Reinoso-Suarez five coronal sections within this range showed a marked congruence between the two atlases.

Animals↗

PubMed1999

Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats.

The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function.

Adrenal Glands↗

PubMed2001

Morphine induces short-lived changes in G-protein gene expression in rat prefrontal cortex.

We have utilized a reverse transcriptase-polymerase chain reaction (RT-PCR) methodology followed by enzymatic restriction analysis to detect changes in G-protein mRNA levels in morphine-treated rats. The relative distribution of mRNA levels for Galpha(o) Galpha(i1), Galpha(i2), Gbeta(1) and Gbeta(2) in the nucleus accumbens, striatum, locus coeruleus and prefrontal cortex was found to be similar to that previously estimated with other techniques. Morphine-induced changes of G-protein mRNA levels were detected only in the prefrontal cortex. Acute treatments (30 mg/kg, intraperitoneally) resulted in a significant increase of Galpha(o) mRNA and significant decreases of Galpha(i1) and Galpha(i2) mRNAs. Chronic morphine administration (10-50 mg/kg over 14 days, intraperitoneally) increased Gbeta(1) and Galpha(i1) and Galpha(i2) mRNAs levels to 148%, 410% and 451% of control, respectively. G-protein mRNA returned to control levels within 48 h of termination of the chronic treatments. The morphine-induced changes in G-protein mRNA levels may reflect changes in gene expression and could result in changes in G-protein levels affecting signal transduction pathways in chronically treated animals.

Animals↗

PubMed1996

Morphine and naloxone, i.p. or locally, affect extracellular acetylcholine in the accumbens and prefrontal cortex.

In rats with microdialysis probes in the nucleus accumbens (NAc) or prefrontal cortex (PFC), intraperitoneally (IP) delivered morphine on the 8th day of escalating doses decreased extracellular ACh in the NAc. On day 9, naloxone (5 mg/kg) precipitated withdrawal and increased the release of ACh. When morphine and methylnaloxonium were given locally into the NAc by reverse dialysis, the opiate again decreased extracellular ACh, and the opiate antagonist increased it. These effects were proportional to the dose of local infusions. Local morphine had the same ACh-lowering effect in morphine-dependent and nondependent rats, whereas local methylnaloxonium increased extracellular ACh significantly more in morphine-dependent animals. Systemic and local effects on ACh systems in the PFC were more complicated and showed some relation to locomotor activity. The results suggest that intrinsic ACh neurons in the NAc have a special relationship to opiate reinforcement such that extracellular ACh is low in response to morphine and high during withdrawal. Thus, low ACh may correlate with opiate reward, and high ACh with aversion.

Acetylcholine↗

PubMed2001

Fast spiking and regular spiking neural correlates of fear conditioning in the medial prefrontal cortex of the rat.

In order to investigate whether and how medial prefrontal cortex (mPFC) of the rat is involved in processing of information related to fear conditioning, we recorded from single units in the prelimbic and infralimbic cortex of fear-conditioned rats in response to an explicit conditional stimulus (CS; an auditory tone) or contextual cues (conditioning box). The majority of units changed their activities significantly in response to the CS in a delay or trace conditioning paradigm. Both transient and tonic activity changes, including delay cell activity, were observed as in other behavioral tasks. When exposed to the context without CS delivery, most units changed their activities as well. These results show that both tone and contextual information are processed in the rat mPFC in expectation of the delivery of an aversive stimulus (electric foot shock). Interestingly, fast spiking cells (putative inhibitory interneurons) and regular spiking cells (putative projection neurons) showed different patterns of responses. Fast spiking cells tended to show transient responses and increased their firing rates following CS presentation, whereas a complementary pattern was observed in the regular spiking cells. Our results enhance our understanding of the neural mechanisms underlying prediction of an aversive stimulus in the mPFC.

Acoustic Stimulation↗

PubMed1997

A parametric study of prefrontal cortex involvement in human working memory.

Although recent neuroimaging studies suggest that prefrontal cortex (PFC) is involved in working memory (WM), the relationship between PFC activity and memory load has not yet been well-described in humans. Here we use functional magnetic resonance imaging (fMRI) to probe PFC activity during a sequential letter task in which memory load was varied in an incremental fashion. In all nine subjects studied, dorsolateral and left inferior regions of PFC were identified that exhibited a linear relationship between activity and WM load. Furthermore, these same regions were independently identified through direct correlations of the fMRI signal with a behavioral measure that indexes WM function during task performance. A second experiment, using whole-brain imaging techniques, both replicated these findings and identified additional brain regions showing a linear relationship with load, suggesting a distributed circuit that participates with PFC in subserving WM. Taken together, these results provide a "dose-response curve" describing the involvement of both PFC and related brain regions in WM function, and highlight the benefits of using graded, parametric designs in neuroimaging research.

Adolescent↗

PubMed2006

Dorsolateral prefrontal cortex and anterior cingulate cortex white matter alterations in late-life depression.

BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) are critical for mood regulation. Alterations in the white matter connections of these regions may impair their role in mood regulation and increase the risk of developing depression. This study used diffusion tensor imaging to examine for white matter microstructural abnormalities of these regions and of central white matter structures in late-life depression. METHODS: One hundred six elderly depressed subjects and eighty-four elderly nondepressed subjects underwent clinical assessment and diffusion tensor imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the DLPFC, ACC, corpus callosum, and internal capsule. Differences between groups were assessed, controlling for age, sex, and total cerebral volume. RESULTS: After controlling for covariates, depressed subjects had significantly lower FA values in white matter of the right ACC, bilateral superior frontal gyri, and left middle frontal gyrus. There were no significant differences in ADC values. CONCLUSIONS: Lower FA, representing lower tissue organization, is observed in depressed elders in the DLPFC and right ACC. These findings support the hypothesis that altered connectivity between brain regions contributes to the risk of depression.

Aged↗

PubMed2004

Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Deoxyribonucleic acid microarray analyses of dorsolateral prefrontal cortex (DLPFC) area 9 from 10 matched pairs of schizophrenic and control subjects revealed a consistent and significant decrease (p = .001; mean log2 signal difference = -.58) in transcript expression for a gene clone KIAA0417. This database entry has been recently annotated as two highly homologous members of a heat-shock protein family (HSPA12A and HSPA12B). METHODS: We followed up our initial results by in situ hybridization in subjects with schizophrenia, major depression, and a chronic haloperidol-treated nonhuman primate model. Furthermore, we investigated the distribution of HSPA12A and HSPA12B transcripts across the human and nonhuman primate brain. RESULTS: We found that HSPA12A (but not HSPA12B) is highly expressed in the human brain and shows a neuron- and region-specific transcript distribution, with strongest expression in the frontal and occipital cortical regions. HSPA12A messenger ribonucleic acid was significantly reduced (p < .01; mean log2 optical density difference = -.84) across subjects with schizophrenia but not in the DLPFC of subjects with major depression or in monkeys chronically treated with haloperidol. CONCLUSIONS: The data are consistent with metabolic alterations in schizophrenia, reflected in selective changes in the expression of certain genes encoding proteins involved in cellular metabolism or metabolic responsiveness.

Adult↗

PubMed2005

Cue familiarity is represented in monkey medial prefrontal cortex during visuomotor association learning.

To examine functional roles of the medial prefrontal cortex (mPFC) in visuomotor association learning, neuronal activity in the mPFC of a behaving monkey was recorded during this learning. The monkey was presented a cueing visual stimulus, and required to push, pull or turn a manipulator according to the cue following a delay period. Under the control condition, three cues (circle, triangle and square) instructed the monkey to the three responses in a block of trials. After 2 months of training the animal was familiar with these cue-response associations. Under the learning condition, two of the three familiar cues and one novel cue were presented in a block. The monkey initially did not know what the novel cue instructed at first and learned a new cue-response association by trial and error. Neurons in the mPFC showed marked responses to cue presentation, and cue responses changed depending on whether cues were familiar or novel. A group of mPFC neurons responded to novel cues, but not to familiar cues. Another group of neurons responded to familiar cues, but not to novel cues. In a subgroup of these familiar cue-selective neurons, cue response was increased under the learning condition compared to the control condition. These results suggest that mPFC neurons differentiate between familiar and novel instructions, and that the neurons responsive to familiar stimuli enhance their modulations when both familiar and novel instructions have to be processed during task performance.

Action Potentials↗

PubMed2003

Muscarinic potentiation of GABA(A) receptor currents is gated by insulin signaling in the prefrontal cortex.

Cholinergic neurotransmission and insulin signaling in cognitive areas, such as the prefrontal cortex (PFC), play a key role in regulating learning and memory. However, the cellular mechanisms by which this regulation occurs are unclear. Because GABAergic inhibition in the PFC controls the timing of neuronal activity during cognitive operations, we examined the potential regulation of GABA transmission by cholinergic and insulin signaling in PFC pyramidal neurons. Activation of muscarinic acetylcholine receptors (mAChRs) with carbachol produced an enhancement of GABA(A) receptor currents in acutely dissociated cells after a short treatment with insulin. Inhibiting phosphoinositide-3 kinase (PI3K), a downstream target of insulin signaling, eliminated this effect as well as the carbachol-induced enhancement of GABAergic miniature IPSC amplitudes in PFC slices. The muscarinic potentiation of GABA(A) currents was blocked by PKC inhibitors, broad-spectrum protein tyrosine kinase inhibitors, and specific inhibitors of the nonreceptor tyrosine kinase Src. Additionally, muscarinic receptors in PFC slices activated PKC and the focal adhesion kinase Pyk2 (a potential molecular link between PKC and Src) in a PI3K-dependent manner. Together, our results show that mAChR activation in PFC pyramidal neurons enhances GABA(A) receptor functions through a PKC-dependent, Src-mediated signaling cascade that is gated by an insulin/PI3K pathway. Given the significance of GABAergic transmission in regulating PFC functions, our results provide a novel mechanism for understanding the role of cholinergic systems and insulin signaling in learning and memory.

Animals↗