PFC Neurons Research Articles

Alpha2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents.

Stimulation of alpha(2)-noradrenergic (NA) receptors within the PFC improves working memory performance. This improvement is accompanied by a selective increase in the activity of PFC neurons during delay periods, although the cellular mechanisms responsible for this enhanced response are largely unknown. Here we used current and voltage clamp recordings to characterize the response of layer V-VI PFC pyramidal neurons to alpha(2)-NA receptor stimulation. alpha(2)-NA receptor activation produced a small hyperpolarization of the resting membrane potential, which was accompanied by an increase in input resistance and evoked firing. Voltage clamp analysis demonstrated that alpha(2)-NA receptor stimulation inhibited a caesium and ZD7288-sensitive hyperpolarization-activated (HCN) inward current. Suppression of HCN current by alpha(2)-NA stimulation was not dependent on adenylate cyclase but instead required activation of a PLC-PKC linked signalling pathway. Similar to direct blockade of HCN channels, alpha(2)-NA receptor stimulation produced a significant enhancement in temporal summation during trains of distally evoked EPSPs. These dual effects of alpha(2)-NA receptor stimulation - membrane hyperpolarization and enhanced temporal integration - together produce an increase in the overall gain of the response of PFC pyramidal neurons to excitatory synaptic input. The net effect is the suppression of isolated excitatory inputs while enhancing the response to a coherent burst of synaptic activity.

Differential modulation of anterior cingulate cortical activity by afferents from ventral tegmental area and mediodorsal thalamus

A distinct increase in cell firing activity is reported in prefrontal cortex during working memory tasks. The afferents that modulate this activity are not yet identified. Using in vivo intracellular recording and labelling of prefrontal cortical pyramidal neurons in anaesthetized rats, we systematically evaluated the influences of afferent projections arising from the ventral tegmental area (VTA) and mediodorsal thalamus (MD) by phasic electrical stimulation with a range of stimulus frequencies. Both VTA- and MD-responsive pyramidal neurons exhibited extensive intracortical axon arborization. Neither single shocks to the VTA at 0.2 Hz, nor low frequency trains of stimuli at 1-4 Hz (< 5 Hz) interrupted the periodicity of membrane bistability in bistable pyramidal neurons. However, high-frequency VTA-train stimulation (10-50 Hz) interrupted the bistability, and produced sustained membrane depolarizations accompanied by intense tonic firing in a frequency-dependent manner. Electrical stimulation of MD (10-50 Hz) did not produce sustained activity in the same PFC neurons. Thus, the sustained activity induced by high-frequency VTA trains is input selective. This effect of VTA-train stimulation was attenuated by systemic injection of the D1 receptor antagonist, SCH 23390, and blocked by acute dopamine (DA) depletion produced via alpha-methyl-para-tyrosine pre-treatment, suggesting that sustained cortical activity is mediated by DA. Chemical stimulation of VTA via intra-VTA infusion of NMDA induced sustained activity similar to VTA-train stimulation. Thus, while both VTA- and MD-responsive pyramidal neurons exhibited extensive intracortical axon arborization, VTA synapses (as opposed to MD synapses) may be critically positioned in the dendritic arborizations of anterior cingulate cortical pyramidal neurons, which may allow their modulation of sustained activity in prefrontal bistable neurons.

S.07.08 Brain networks in sleep as revealed by combined EEG and fMRI

Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy individuals and behavioral abnormalities with corresponding symptoms of schizophrenia in non-human animals. Our previous studies showed that systemically administered PCP produces tonic activation of neurons in the medial prefrontal cortex (mPFC) of rats and that this activation is mainly via excitatory inputs from regions outside the mPFC. Such long-lasting activation of PFC neurons is now considered to be a pivotal factor in PCP-induced behavioral abnormalities. Although our previous study identified the ventral hippocampus as a possible source of the excitatory inputs, it is not the only source innervating the mPFC. Several regions such as the thalamus also have monosynaptic projections to the mPFC. Recently, increased c-fos expression by systemic PCP administration was reported in the mediodorsal nucleus of the thalamus (MD) and the centromedial nucleus of the thalamus (CM), which have strong reciprocal innervations with the mPFC. However, few studies have reported effects of PCP on the firing activity of MD/CM neurons in unanesthetized animals. In the current study in freely moving rats, we examined effects of systemically administered PCP on the spontaneous firing activity of the MD/CM, after identifying the response properties of recorded neurons in social interaction with an unfamiliar partner. About 30% of MD/CM neurons recorded exhibited tonic excitation following systemic PCP administration, whereas only a few neurons (7%) were inhibited by PCP. The proportion of MD neurons activated by systemic PCP administration was about half of that in the mPFC. Although the proportion of neurons responsive to social interaction did not differ between the two regions (40%), neurons activated during social interaction in the mPFC (90%) were more likely to be affected by systemic PCP administration than those in the MD/CM (45%). These results suggest that neurons responsive to social interaction in the mPFC may be differently affected by PCP than those in the MD/CM.

Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway.

Phencyclidine (PCP) is a psychotomimetic drug that elicits schizophrenia-like symptoms in healthy persons, and administration of PCP to animals is used as a pharmacological model of schizophrenia. We recently demonstrated that systemic administration of PCP to rats produces long-lasting activation of medial prefrontal cortex (mPFC) neurons with augmentation of locomotor activity, whereas direct application of PCP to mPFC neurons has little effect on their firing activity. These findings suggest that PCP-induced activation of mPFC neurons is elicited mainly via excitatory inputs from regions outside the mPFC. In the present study, we examined effects of local application of PCP to the ventral hippocampus (vHIP) on firing activity of PFC neurons in freely moving rats. PCP locally perfused into the vHIP increased spontaneous discharges of PFC neurons during perfusion with augmentation of locomotor activity. Local application of a more selective NMDA receptor antagonist, MK801, to vHIP neurons under anesthesia increased the spontaneous firing rates of most neurons directly projecting to the mPFC, whereas local application of MK801 to mPFC neurons did not induce excitatory responses in any of those neurons. The present results indicate that tonic excitatory inputs from the vHIP to the PFC may trigger development of behavioral abnormalities.

Dopamine modulates inwardly rectifying potassium currents in medial prefrontal cortex pyramidal neurons.

Dopamine (DA) modulation of excitability in medial prefrontal cortex (mPFC) pyramidal neurons has attracted considerable attention because of the involvement of mPFC DA in several neuronal disorders. Here, we focused on DA modulation of inwardly rectifying K(+) current (IRKC) in pyramidal neurons acutely dissociated from rat mPFC. A Cs(+)-sensitive whole-cell IRKC was elicited by hyperpolarizing voltage steps from a holding potential of -50 mV. DA (20 microm) reduced IRKC amplitude, as did selective stimulation of DA D(1) or D(2) class receptors (D(1)Rs and D(2)Rs). D(1)Rs activate, whereas D(2)Rs inhibit, the adenylyl cyclase-cAMP-protein kinase A (PKA) signaling pathway. Suppression of IRKC by D(2)R stimulation was attributable to decreased PKA activity because similar inhibition was observed with PKA inhibitors, whereas enhancing PKA activity increased IRKC. This suggests that the DA D(1)R suppression of IRKC occurred through a PKA phosphorylation-independent process. Using outside-out patches of mPFC pyramidal neurons, which preclude involvement of cytosolic signaling molecules, we observed a Cs(+)-sensitive macroscopic IRKC that was suppressed by the membrane-permeable cyclic nucleotide Sp-cAMP but was unaffected by non-nucleotide modulators of PKA, suggesting direct interactions of the cyclic nucleotides with IRK channels. Our results indicate that DA suppresses IRKC through two mechanisms: D(1)R activation of cAMP and direct interactions of the nucleotide with IRK channels and D(2)R-mediated dephosphorylation of IRK channels. The DA modulation of IRKC indicates that ambient DA would tend to increase responsiveness to excitatory inputs when PFC neurons are near the resting membrane potential and may provide a mechanism by which DA impacts higher cognitive function.

What information is represented by prefrontal neuronal activity?

Working memory is a mechanism for short-term active storage of information and for processing stored information. Although evidence for temporary storage mechanisms of information has been accumulated, little is known about neuronal mechanisms for processing information. To understand how information is processed in the nervous system, we first need to know what information single-neuron activity represents, then examine how represented information by single-neuron activities changes along the temporal sequence of the trial. We used two kinds of culomotor delayed-response (ODR) tasks and examined what information prefrontal single-neuron activity represents. We found that all cue-period activity encoded cue positions. However, among neurons, which exhibited delay-period activity, 86% encoded cue positions, while 13% encoded saccade directions. In addition, among neurons exhibiting oculomotor activity, 58% encoded saccade directions, while 35% encoded cue positions. To visualize temporal patterns of changes of information represented by a population of prefrontal neurons, we analyzed single-neuron activities using a population vector analysis. As a result, we found that information represented by a population of PFC neurons changes gradually during the delay period from information for visual cue to that for saccade.

Medial prefrontal cortical output neurons to the ventral tegmental area (VTA) and their responses to burst-patterned stimulation of the VTA: neuroanatomical and in vivo electrophysiological analyses.

During a delayed period in a delayed-response task, prefrontal cortical neurons show a change in neuronal firing rate that is dependent on a functional mesocortical dopamine input. This change in firing rate has been attributed to be part of the cellular processes underlying working memory. However, it is unclear what neural mechanisms activate mesocortical dopamine neurons to provide an optimal level of dopamine to modulate the firing of the medial prefrontal cortical (mPFC) neurons. This study examined the possibility of whether mPFC neurons that project to the ventral tegmental area (VTA) might activate the ascending mesocortical dopamine neurons. To determine the locations of the mPFC-->VTA neurons, cholera toxin subunit B was microinjected into the VTA. Retrogradely labeled mPFC neurons mainly reside in the deep lamina V and VI. In vivo single unit recording in urethane-anesthetized rats were also used to determine the responses of some of these neurons to burst-patterned stimulation of the VTA. Single-pulse stimulation (1 Hz) of the VTA antidromically activated burst firing mPFC-->VTA neurons. In response to burst-patterned stimulation of the VTA, which mimicked burst firing of VTA dopamine neurons (4-10 pulses at 10-15 Hz cycled at 0.5-3 Hz), the temporal structure of spontaneous burst firing patterns of these neurons but not their mean firing rate were changed. However, the mean firing rate of the non-VTA projecting neurons (i.e., no antidromic response to VTA stimulations) was either increased or decreased by similar burst-patterned stimulation of the VTA. These data suggest that burst-patterned stimulation of the ascending VTA-->mPFC or putative mesocortical dopamine neurons might have released dopamine and/or other neuromodulators to modulate the temporal code, rather than the rate code, of mPFC-->VTA neurons. Medial PFC neurons that project elsewhere (e.g., nucleus accumbens or mediodorsal thalamus) may mediate the sustained firing rate changes during, e.g., short-term working memory.

Treatment of benign prostatic hyperplasia: Author's reply

Neurons in the PFC are typically activated by different cognitive tasks, and also by different stimuli and abstract variables within these tasks. A single neuron9s selectivity for a given stimulus dimension often changes depending on its context, a phenomenon known as nonlinear mixed selectivity (NMS). It has previously been hypothesized that NMS emerges as a result of training to perform tasks in different contexts. We tested this hypothesis directly by examining the neuronal responses of different PFC areas before and after male monkeys were trained to perform different working memory tasks involving visual stimulus locations and/or shapes. We found that training induces a modest increase in the proportion of PFC neurons with NMS exclusively for spatial working memory, but not for shape working memory tasks, with area 9/46 undergoing the most significant increase in NMS cell proportion. We also found that increased working memory task complexity, in the form of simultaneously storing location and shape combinations, does not increase the degree of NMS for stimulus shape with other task variables. Lastly, in contrast to the previous studies, we did not find evidence that NMS is predictive of task performance. Our results thus provide critical insights on the representation of stimuli and task information in neuronal populations, in working memory. <b>SIGNIFICANCE STATEMENT</b> How multiple types of information are represented in working memory remains a complex computational problem. It has been hypothesized that nonlinear mixed selectivity allows neurons to efficiently encode multiple stimuli in different contexts, after subjects have been trained in complex tasks. Our analysis of prefrontal recordings obtained before and after training monkeys to perform working memory tasks only partially agreed with this prediction, in that nonlinear mixed selectivity emerged for spatial but not shape information, and mostly in mid-dorsal PFC. Nonlinear mixed selectivity also displayed little modulation across either task complexity or correct performance. These results point to other mechanisms, in addition to nonlinear mixed selectivity, representing complex information about stimulus and task context in neuronal activity.