Activity Of Prefrontal Cortical Neurons Research Articles

Gastrointestinal mechanosensation affects the activity of prefrontal cortical neurons mediating social behavior in mice

Social cognition requires integration of sensory modalities with emotion and experience to plan and engage in appropriate social behavior. Oxytocin is a neuropeptide that shapes the perception of social stimuli by activating the oxytocin receptor (Oxtr). Neurons within the medial prefrontal cortex (mPFC) that express Oxtr(s) (referred to as mPFCOxtr) integrate these complex systems. Oxytocin acts within the brain to influence the perception of the external environment; however, Oxtr(s) are also expressed on vagal sensory afferents, suggesting that oxytocin may also influence interoception or the ability to sense one’s internal state. To better understand the role of interoception in social cognition, we examined the structure and function of the neurons within the nodose ganglia that express the Oxtr (referred to as NDGOxtr). To visualize NDGOxtr, we bilaterally injected Cre‐inducible adeno‐associated virus (AAV) synthesizing mCherry or tdTomato into the nodose ganglia (NDG) of mice with Cre‐recombinase directed to the Oxtr gene (Oxtr‐Cre mice). We found that NDGOxtr expressed mRNAs for the mechanically gated ion channels, Piezo 1/2, and sent fibers to the stomach and duodenum that formed intramuscular arrays or intraganglionic laminar endings. These results suggest that NDGOxtr function as mechanoreceptors that detect distention of the gastrointestinal tract. Next, we used in vivo Ca2+ imaging to determine the effect that gastric distention has on mPFCOxtr that mediate social behavior. Oxtr‐Cre mice were delivered Cre‐inducible AAV expressing the fluorescent Ca2+ indicator, GCaMPf, into the mPFC, and subsequently, implanted with a GRIN lens. After habituation to the head mounted miniscope, mice were tested in the social interaction paradigm and Ca2+ events were recorded. Receiver operating characteristic analysis revealed that ≍30% of mPFCOxtr couple firing to social interaction. Next, we evaluated how gastric distention may influence the activity of mPFCOxtr. Mice were given a sham gavage or a gavage of methylcellulose and Ca2+ events from mPFCOxtr were recorded. Differences in Ca2+ events were calculated using a Wilcoxon rank sum test to the classify individual neurons as inhibited, excited, or unchanged by the stimulus. Intriguingly, gavage of methylcellulose robustly inhibited mPFCOxtr relative to the sham‐treated control. To determine whether NDGOxtrmediate this inhibition, Oxtr‐Cre mice outfitted for in vivo Ca2+ imaging were given Cre‐inducible AAV expressing channelrhodopsin2 into the NDG and a fiber optic was implanted into the nucleus of the solitary tract (NTS). This approach enables optogenetic excitation of axons in the NTS originating from NDGOxtr during simultaneous Ca2+ imaging of mPFCOxtr. Preliminary results indicate that optogenetic excitation of NDGOxtr also inhibit mPFCOxtr. Collectively, our results suggest that mechanosensation of the gastrointestinal tract may have a profound influence over the perception of social stimuli.

Disruption of columnar and laminar cognitive processing in primate prefrontal cortex following cocaine exposure.

Prefrontal cortical activity in primate brain plays a critical role in cognitive processes involving working memory and the executive control of behavior. Groups of prefrontal cortical neurons within specified cortical layers along cortical minicolumns differentially generate inter- and intra-laminar firing to process relevant information for goal oriented behavior. However, it is not yet understood how cocaine modulates such differential firing in prefrontal cortical layers. Rhesus macaque nonhuman primates (NHPs) were trained in a visual delayed match-to-sample (DMS) task while the activity of prefrontal cortical neurons (areas 46, 8 and 6) was recorded simultaneously with a custom multielectrode array in cell layers 2/3 and 5. Animals were reinforced with juice for correct responses. The first half of the recording session (control) was conducted following saline injection and in the second half of the same session cocaine was administered. Prefrontal neuron activity with respect to inter- and intra-laminar firing in layers 2/3 and 5 was assessed in the DMS task before and after the injection of cocaine. Results showed that firing rates of both pyramidal cells and interneurons increased on Match phase presentation and the Match Response (MR) in both control and cocaine halves of the session. Differential firing under cocaine vs. control in the Match phase was increased for interneurons but decreased for pyramidal cells. In addition, functional’ interactions between prefrontal pyramidal cells in layer 2/3 and 5 decreased while intra-laminar cross-correlations in both layers increased. These neural recordings demonstrate that prefrontal neurons differentially encode and process information within and between cortical cell layers via cortical columns which is disrupted in a differential manner by cocaine: administration.

Working Memory Impairment in Calcineurin Knock-out Mice Is Associated with Alterations in Synaptic Vesicle Cycling and Disruption of High-Frequency Synaptic and Network Activity in Prefrontal Cortex

Working memory is an essential component of higher cognitive function, and its impairment is a core symptom of multiple CNS disorders, including schizophrenia. Neuronal mechanisms supporting working memory under normal conditions have been described and include persistent, high-frequency activity of prefrontal cortical neurons. However, little is known about the molecular and cellular basis of working memory dysfunction in the context of neuropsychiatric disorders. To elucidate synaptic and neuronal mechanisms of working memory dysfunction, we have performed a comprehensive analysis of a mouse model of schizophrenia, the forebrain-specific calcineurin knock-out mouse. Biochemical analyses of cortical tissue from these mice revealed a pronounced hyperphosphorylation of synaptic vesicle cycling proteins known to be necessary for high-frequency synaptic transmission. Examination of the synaptic vesicle cycle in calcineurin-deficient neurons demonstrated an impairment of vesicle release enhancement during periods of intense stimulation. Moreover, brain slice and in vivo electrophysiological analyses showed that loss of calcineurin leads to a gene dose-dependent disruption of high-frequency synaptic transmission and network activity in the PFC, correlating with selective working memory impairment. Finally, we showed that levels of dynamin I, a key presynaptic protein and calcineurin substrate, are significantly reduced in prefrontal cortical samples from schizophrenia patients, extending the disease relevance of our findings. Our data provide support for a model in which impaired synaptic vesicle cycling represents a critical node for disease pathologies underlying the cognitive deficits in schizophrenia.

Iontophoresis of lithium antagonizes noradrenergic action on prefrontal neurons of the rat

Various lithium (Li +) compounds have been proven to be effective in the therapy of bipolar affective disorder, but their mechanism of pharmacological action is not clearly defined. In our present in vivo electrophysiological study we tested the action of microiontophoretically applied Li + and NE on the maintained firing activity of prefrontal cortical neurons of the rat. Target cells were located in the prelimbic cortical projection region (PrL) of the ascending norepinephrinergic pathway. Our data, collected from single unit activity of 59 PrL neurons, demonstrate that lithium can (1) suppress maintained discharge activity, or (2) antagonize both the inhibitory and excitatory modulation of firing activity elicited by NE. These effects of Li + were not replicable with GABA-initiated inhibition or glutamate analogue-initiated excitation of discharge activity. Our findings suggest that the action of Li + mainly targets the NE-coupled receptor mechanisms and, therefore, it may play an important role in stabilizing the modulation of discharge activity in the PFC caused by different extracellular levels of NE.

Post-cue activity of prefrontal cortical neurons controlled by local inhibition

With a model of the prefrontal cortical circuit, proposed here, this paper investigates the post-cue (delay-period) activity of the prefrontal cortical neurons for a spatial working memory task. The computer simulations of the model circuit show that a slight change in the strength of the local inhibition dramatically alters the post-cue activity as well as the tuning properties of the model prefrontal cortical neurons. Appropriate regulation of the local inhibition is necessary to form and maintain spatial working memory. These results suggest the capability of the local inhibition to play an important role in the active control of working memory.

Noradrenergic Effects on Activity of Prefrontal Cortical Neurons in Behaving Monkeys

This chapter summarizes that iontophoretic application of the α 2 -receptor antagonist yohimbine to prefrontal neurons in the monkey attenuated delay-period activity, indicating that activation of α 2 receptors plays a critical role in maintaining the directional or mnemonic coding of prefrontal neurons. Of 57 neurons recorded during oculomotor delayed-response (ODR) performance, the researchers concentrate on 31 neurons that showed delay-period activity of which magnitude differed significantly with the direction of cue-response, because such directional delay-period activity has been suggested to play a central role in the working memory process for visuospatial information. These neurons are located in the principal sulcus or immediately adjacent cortex. It has been demonstrated that iontophoretic application of the selective α 2 -adrenergic receptor antagonist, yohimbine, attenuate the directional delay-period activity of prefrontal neurons during ODR performance. At the same time, yohimbine attenuated the sharpness of directional tuning, examined by fitting to a cosine function, of directional delay-period activity. These findings suggest that the activation of α 2 receptors plays a modulatory role in maintaining the directional tuning of delay-period activity of prefrontal cortical neurons during ODR performance. As the directional delay-period activity with tuning is considered to represent mnemonic coding for visuospatial working memory, it can be concluded that the activation of α 2 receptor plays a modulatory role in maintaining mnemonic coding of neuronal activity for the working-memory process in primate prefrontal cortex.

Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: Evidence for the involvement of both dopaminergic and GABAergic components

The medial prefrontal cortex of the rat receives dopamine and non-dopaminergic projections from the ventral tegmental area. Both electrical stimulation of the ventral tegmental area and local application of dopamine induce an inhibition of the spontaneous activity of most prefrontal cortical neurons, including efferent neurons. In the present study, the techniques of extracellular recording and microiontophoresis were used in anesthetized rats in order to determine whether these dopamine- and ventral tegmental area-induced inhibitory responses involve GABAergic components. Prefrontal cortex output neurons were identified by antidromic activation from subcortical structures. The inhibitory responses evoked by the local application of dopamine were blocked by the iontophoretic application of the D 2 antagonist sulpiride, and the GABA A antagonist bicuculline in 89 and 57% of the cases, respectively. In addition, sulpiride and bicuculline abolished the inhibition induced by ventral tegmental area stimulation in 54 and 51% of the prefrontal cortical cells tested, respectively. The implication of a non-dopaminergic mesocortical system in the ventral tegmental area-induced inhibition was further analysed using rats pre-treated with α-methylparatyrosine to deplete dopamine stores. The proportion of prefrontal cortical cells inhibited by ventral tegmental area stimulation was markedly reduced (39%) in α-methylparatyrosine-treated rats, when compared to controls (86%). Remaining ventral tegmental area-induced inhibition was no longer affected by sulpiride, but in all cases blocked by the local microiontophoretic application of bicuculline. The present results suggest that: (1) the dopamine-induced inhibition of prefrontal cortex neurons could involve cortical GABAergic interneurones; (2) the non-dopaminergic mesocortical system exerts also an inhibitory influence on prefrontal cortical cells and appears to be GABAergic.

Differential effects of ascending neurons containing dopamine and noradrenaline in the control of spontaneous activity and of evoked responses in the rat prefrontal cortex

The medial prefrontal cortex receives converging projections from the mediodorsal thalamic nucleus, dopaminergic cells from the ventral tegmental area and noradrenergic cells from the locus coeruleus. Stimulation of the ventral tegmental area inhibits the spontaneous activity of prefrontal cortical neurons and blocks the excitatory response evoked by stimulation of the mediodorsal thalamic nucleus (10 Hz). The aim of the present study was to compare the influence of dopaminergic and noradrenergic afferents on the spontaneous and evoked activity of medial prefrontal cortical neurons. In ketamine-naesthetized rats, repetitive stimulation (20 Hz, 10 s) of the locus coeruleus produced a long-lasting post-stimulus inhibition (mean duration: 45 s) of the spontaneous activity of 56% of the tested cells. This effect was decreased markedly following selective destruction of the ascending noradrenergic pathways (local 6-hydroxy-dopamine injection) or depletion of cortical catecholamines by α-methyl- para-tyrosine pretreatment, suggesting that these inhibitory responses are mediated by noradrenergic neurons. The excitatory response to mediodorsal thalamus nucleus stimulation (10 Hz) could still be evoked during the post-stimulus inhibitory period induced by locus coeruleus stimulation (20 Hz, 10 s) resulting in the enhancement of signal-to-noise ratio. On the other hand, a population of prefrontal cortex neurons (26%) was found to be reproducibly activated by noxious tail pinch. This evoked response was still present during the post-stimulus inhibitory period induced by locus coeruleus stimulation but was completely suppressed during stimulation of the ventral tegmental area (10 Hz). In conclusion, these results indicate that the dopaminergic and noradrenergic systems exert a completely distinct control of information transfer in the medial prefrontal cortex.

Chemical Nature of Synaptic Transmission in Vertebrates

Chemical Nature of Synaptic Transmission in Vertebrates