1,720,964 research outputs found
Real-time biosensing of glutamatergic and cholinergic neurotransmission in vivo: implications for psychopharmacology
No full textReal-time biosensing of glutamatergic and cholinergic neurotransmission in vivo: implications for psychopharmacology
Real-time biosensing of glutamatergic and cholinergic neurotransmission in vivo: implications for psychopharmacology
No full textReal-time biosensing of glutamatergic and cholinergic neurotransmission in vivo: implications for psychopharmacology
Regulation and function of the tonic component of cortical acetylcholine release
No full textRegulation and function of the tonic component of cortical acetylcholine release
Multiple time scales and variable spaces: synaptic neurotransmission in vivo
No full textRegulation and function of the tonic component of cortical acetylcholine release
Multiple modes of cholinergic neurotransmission - Multiple functions
No full textStimulation of nAChRs has been widely suggested as a new approach to treat the cognitive symptoms of a range of disorders. Our current model postulates two separate modes of cholinergic neurotransmission. First, a tonic component (changes over minutes; measured by microdialysis) of cholinergic activity modulates the gain of thalamic input processing, via stimulation of α4β2* nAChRs expressed by thalamic afferents. Second, cue-evoked glutamate release from thalamic afferents generates transient (seconds) increases in acetylcholine (ACh) release (measured by amperometry and enzyme-coated microelectrodes). Glutamatergic and cholinergic transients interact to enhance the probability and efficacy of cue detection. The tonic component of cholinergic activity is hypothesized to modulate the general readiness for cortical input processing (or “arousal”), by modulating the “neuronal salience” of the cue. The present experiments were designed to specify the regulation and role of the tonic component of cholinergic neurotransmission. To this end, we studied the behavioral/cognitive and cholinergic effects of the selective α7 nAChR agonist ABT-107, known to evoke lasting increases in tonic cholinergic activity in naïve animals, and the selective α4β2* nAChR agonist ABT-089, known to augment cholinergic transients in animals detecting cues. In animals conditioned to a simple arousing stimulus (darkness+palatable food), administration of ABT-107, but not ABT-089 increased basal and augmented stimulus-evoked increases in ACh release and increased exploratory activity. ABT-107 did not affect sustained attention performance, (SAT)-associated increases in ACh release and mildly impaired performance. ABT-089 enhanced SAT performance in non-tethered animals while lowering performance-associated increases in ACh release. These results suggest that the “arousal”-enhancing effects of increases in tonic cholinergic activity are restricted to situations devoid of behavioral/cognitive constraints. Tonic cholinergic activity supports both spontaneous and cognitive performance; however, tonic cholinergic activity is tightly regulated in cognitive contexts. In cognitive contexts, tonic activity levels are protected against pharmacological manipulation, as indicated by the absence of effects of ABT-107 in SAT performing animals and by reducing cholinergic tone in the presence of an α4β2* nAChR agonist. Finally, the two component of cholinergic activity do not necessarily co-vary, and that drug effects on cholinergic activity in naïve animals do not predict effects on cognitive performance-mediating cholinergic neurotransmission
Staying cognitively engaged during the wrong time of the day: cognitive-cholinergic induction and maintenance of diurnality in rats
No full textDaily practice of a sustained attention task (SAT) during the light phase of the light/dark cycle causes a stable, entrained, diurnal behavioral activity pattern (Gritton et al. 2009). Following cessation of SAT practice, animals continue to exhibit a diurnal pattern for 8-10 days. As SAT performance is mediated by increases in cortical cholinergic neurotransmission, this experiment assessed levels of acetylcholine (ACh) release across the light and dark cycle of animals that previously performed the SAT at a fixed time. Circadian behavioral activity was recorded, and prefrontal ACh release was measured, using microdialysis, beginning on the third day following the last SAT session. SAT practice took place in either the light phase [ZT4], the dark phase, [ZT16], or in a constant light condition [LL]. A control group practiced a daily fixed interval [FI-9] schedule of reinforcement at ZT4. A second control group was handled at randomly selected times but was neither water-deprived nor performed a task [NP]. Dialysates were collected for 180 min total, beginning 90 min before the prior onset of task practice and again during the equivalent time period twelve hours later. For all animals, ACh release levels were higher during the dark phase. In SAT-performing animals, ACh levels increased for 45 min at ZT4 and ZT16. In addition, the ZT4 animals’ behavioral activity was robustly increased during this interval. Animals trained at ZT4 reversed back to a nocturnal activity pattern 8-10 days after cessation of SAT practice, coinciding with the loss of the task time-synchronized cholinergic activity. A second series of experiments focused on transient increases in cholinergic activity. These transients mediate the actual cue detection process, they are generated by prefrontal glutamatergic-cholinergic interactions, and these interactions are modulated by tonic cholinergic activity such as task time-synchronized increases. Ongoing experiments test the hypothesis that during the prior practice period, spontaneously generated transients occur at a higher frequency, indicative of an enhanced readiness to utilize external cues. Collectively, these results are consistent with the hypothesis that cognitive activity evokes a profound shift of circadian activity and that internal clocks continue to activate the prefrontal attention system precisely at the time of prior practice. Cognitive performance evokes, and is optimized by, synchronization of circadian activity with the performance period. Cholinergic inputs to the cortex mediate performance and also contribute to circadian shifts, and in turn become subject to circadian control
Regulation and function of the tonic component of cortical acetylcholine release.
No full textStudies aiming at corroborating the regulation and function of the cortical cholinergic input system that postulates two separate modes of cholinergic neurotransmission. First a tonic component of cholinergic activity (changes on the scale of minutes) modulates the gain of thalamic input processing via stimulation of alfa4beta2 receptors expressed by thalamic afferents. Second , cue evoked glutamatergic release from thalamic afferents generates phasic or transient (scale of seconds) increases in acetylcholine release via stimulation of ionotropic glutamatergic receptors
Multiple time scales and variable spaces: synaptic neurotransmission in vivo
No full textMonitoring of cholinergic transmission on different time-scal
Optogenetically-evoked cortical cholinergic transients in mice expressing channelrhodopsin-2 (ChR2) in cholinergic neurons.
No full textThe use of enzyme-selective microelectrodes for the real-time amperometric detection of neurotransmitter release has generated new insights in the regulation and function of major neurotransmitter and -modulator systems. We previously demonstrated that transient increases in prefrontal cholinergic activity (scale of seconds) mediate the detection of cues in attention-demanding contexts. This research was designed to determine if the transgenic expression of the photo-sensitive cation channel channelrhodopsin-2 (ChR2) is conducive to electrochemical studies measuring neurotransmitter release in the terminal fields of cholinergic projection neurons. We employed a viral vector to selectively express the ChR2 transgene in cholinergic neurons of the basal forebrain (substantia innominata/nucleus basalis of Meynert). Expression was achieved through the infusion of a DIO-ChR2-YFP construct packaged in an AAV vector into mice expressing the CRE recombinase gene under the control of the ChAT promoter. We employed enzyme-coated microelectrodes and fixed potential amperometry in order to measure the release of acetylcholine evoked by photoactivation of cholinergic neurons. Currents recorded via choline oxidase-coated platinum sites were referenced to adjacent non-coated sites. Light pulses were delivered to the cells expressing ChR2 via a laser diode with a wavelength of 446 nm coupled to a fiber-optic cable (200 μm in diameter) that could be raised or lowered via a micromanipulator on a stereotaxic instrument. Individual light pulses (<1 ms in duration, 5-40 mW as measured at the fiber tip) were insufficient to drive detectable cholinergic transients; however short pulses of light delivered in succession (10-60X) at frequencies greater than 10 Hz resulted in measurable cholinergic signals of 0.5 μM or greater. Electrochemical recordings performed in cortical areas contralateral to the hemisphere expressing ChR2 as well as non-projection ipsilateral regions - such as the striatum - did not yield detectable cholinergic signaling. We conclude that the expression of photoactivated ChR2 can be used to selectively activate cholinergic projections to terminal regions and that this release is detectable using enzyme-selective microelectrodes. Future studies will test the hypothesis that the augmentation of cue evoked cholinergic transients improves attentional task-performance and will yield information about the impact of poorly orchestrated or invalid cholinergic transients on cognitive performance
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