1,721,043 research outputs found
Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance
No full textAlthough the impairments in cognitive performance that result from shifting or disrupting daily rhythms have been demonstrated, the neuronal mechanisms that optimize fixed-time daily performance are poorly understood. We previously demonstrated that daily practice of a sustained attention task (SAT) evokes a diurnal activity pattern in rats. Here, we report that SAT practice at a fixed time produced practice time-stamped increases in prefrontal cholinergic neurotransmission that persisted after SAT practice was terminated and in a different environment. SATtime-stamped cholinergic activation occurred regardless of whether the SAT was practiced during the light or dark phase or in constant-light conditions. In contrast, prior daily practice of an operant schedule of reinforcement, albeit generating more rewards and lever presses per session than the SAT, neither activated the cholinergic system nor affected the animals' nocturnal activity pattern. Likewise, food-restricted animals exhibited strong food anticipatory activity (FAA) and attenuated activity during the dark phase but FAA was not associated with increases in prefrontal cholinergic activity. Removal of cholinergic neurons impaired SAT performance and facilitated the reemergence of nocturnality. Shifting SAT practice away from a fixed time resulted in significantly lower performance. In conclusion, these experiments demonstrated that fixed-time, daily practice of a task assessing attention generates a precisely practice time-stamped activation of the cortical cholinergic input system. Time-stamped cholinergic activation benefits fixed time performance and, if practiced during the light phase, contributes to a diurnal activity patter
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
Prior daily practice of a sustained attention task during the light phase evokes a diurnal behavioral activity pattern and a task time-synchronized increase in prefrontal cholinergic neurotransmission
No full textWe recently observed that daily 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). As SAT performance increases cortical acetylcholine (ACh) release, this experiment assessed the influence of the prefrontal ACh on SAT practice-induced diurnality. Circadian behavioral activity was recorded to verify the SAT effect on circadian activity, and prefrontal ACh release was measured, using microdialysis, 3 days following the last practice session. SAT practice occurred either during the light phase [ZT4] or during the dark phase, [ZT16]. A control group practiced a daily fixed interval 9 s [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 every 15 min 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 was higher during the dark phase when compared with the light period. Furthermore, in previously SAT-performing animals, ACh levels increased for 45 min at ZT4 and ZT16. Collectively these results indicate that the diurnal activity pattern that results from SAT practice during the light phase is not mediated via global alterations in the circadian regulation of ACh release. However, prior practice of the SAT established a stable increase in ACh release that lasted as long as the prior SAT sessions, and this task time-synchronized increase in prefrontal cholinergic activity may contribute to the induction or maintenance of diurnality in ZT4 animals. Future research is testing whether removal of cholinergic neurons interferes with ZT4 SAT practice-induced diurnality. Furthermore, it will be important to determine the time point after cessation of SAT practice at which ZT4 animals reverse to a nocturnal pattern and whether this coincides with the loss of task time-synchronized cholinergic activity. This research provides new insights in understanding cognitive work-induced shifts in circadian rhythms, the cause and role of circadian abnormalities in neuropsychiatric disorders, and it eventually will inform the development of treatments of such disorders
Time to pay attention: Attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance
No full textAlthough the impairments in cognitive performance that result from shifting or disrupting daily rhythms have been demonstrated, the neuronal mechanisms that optimize fixed-time daily performance are poorly understood. We previously demonstrated that daily practice of a sustained attention task (SAT) evokes a diurnal activity pattern in rats. Here, we report that SAT practice at a fixed time produced practice time-stamped increases in prefrontal cholinergic neurotransmission that persisted after SAT practice was terminated and in a different environment. SATtime-stamped cholinergic activation occurred regardless of whether the SAT was practiced during the light or dark phase or in constant-light conditions. In contrast, prior daily practice of an operant schedule of reinforcement, albeit generating more rewards and lever presses per session than the SAT, neither activated the cholinergic system nor affected the animals' nocturnal activity pattern. Likewise, food-restricted animals exhibited strong food anticipatory activity (FAA) and attenuated activity during the dark phase but FAA was not associated with increases in prefrontal cholinergic activity. Removal of cholinergic neurons impaired SAT performance and facilitated the reemergence of nocturnality. Shifting SAT practice away from a fixed time resulted in significantly lower performance. In conclusion, these experiments demonstrated that fixed-time, daily practice of a task assessing attention generates a precisely practice time-stamped activation of the cortical cholinergic input system. Time-stamped cholinergic activation benefits fixed time performance and, if practiced during the light phase, contributes to a diurnal activity patter
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
Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: a model of cholinergic capacity limits
No full textReductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/- mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/- mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/- mice. Additionally, CHT+/- mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of α4β2* nAChRs in the cortex of CHT+/- mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/- cholinergic terminals. Further analyses of molecular and functional compensations in the CHT+/- model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders
Deficits in attentional control: Cholinergic mechanisms and circuitry-based treatment approaches.
No full textThe cognitive control of attention involves maintaining task rules in working memory (or "online"), monitoring reward and error rates, filtering distractors, and suppressing prepotent, and competitive responses. Weak attentional control increases distractibility and causes attentional lapses, impulsivity, and attentional fatigue. Levels of tonic cholinergic activity (changes over tens of seconds or minutes) modulate cortical circuitry as a function of the demands on cognitive control. Increased cholinergic modulation enhances the representation of cues, by augmenting cue-evoked activity in thalamic glutamatergic afferents, thereby increasing the rate of detection. Such cholinergic modulation is mediated primarily via α4β2* nicotinic acetylcholine receptors. Animal experiments and clinical trials in adult patients with ADHD indicate that attentional symptoms and disorders may benefit from drugs that stimulate this receptor. Tonic cholinergic modulation of cue-evoked glutamatergic transients in prefrontal regions is an essential component of the brain's executive circuitry. This circuitry model guides the development of treatments of deficits in attentional control. © 2011 American Psychological Association
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
Sampling from injured tissue as a blessing in disguise: tonic changes in cholinergic neurotransmission using microdialysis
No full textPrefrontal cholinergic transmission in damaged and intact tissue from naive and treated rats via in-vivo microdialysi
Sign- versus goal trackers, top down control of attention, and underlying cholinergic mechanisms
No full textThe propensity to attribute incentive salience to reward cues has been hypothesized to indicate vulnerability for addiction-like behavior. Evidence in support of this hypothesis has been obtained from experiments studying animals which, using a Pavlovian conditioned approach test, were categorized as ‘sign-trackers’ (ST). In contrast to ST, ‘goal-trackers’ (GT) do not readily attribute incentive salience to reward cues and are less vulnerable for developing addiction-like behavior. Our research is guided by the hypothesis that ST, when compared with GT, exhibit lower levels of cognitive control of attention, thereby fostering behaviors that interfere with (sustained) attentional performance. Furthermore, as cholinergic modulation of prefrontal circuitry serves as a top-down signal for attention, we hypothesized that attentional performance-associated increases in prefrontal cholinergic neurotransmission are lower in ST than GT. ST and GT were trained and extensively practiced the Sustained Attention Task (SAT). This task consists of signal and non-signal trials and animals are rewarded for hits and correct rejections, respectively, while misses and false alarms trigger the inter-trial interval but have no further scheduled consequences. Asymptotic SAT performance of ST was characterized by lower hit rates when compared with GT. ST more frequently disengaged from orienting toward the intelligence panel, thereby missing signals. Because non-signal trial responding appears to represent the default response mode for all animals, limitations in the ability to sustain attention toward the signal source did not result in lower rates of correct rejections. SAT-associated increases in cholinergic neurotransmission, assessed by using microdialysis, were significantly lower in ST. Because this tonic component of cholinergic neurotransmission modulates prefrontal circuitry via alpha4beta2* nicotinic acetylcholine receptors (nAChRs), we also tested the hypothesis that blocking these receptors in GT disrupts SAT performance. Systemic administration of the relatively beta2*-selective nAChR antagonist dihydro-beta-erythroidine (5.0 mg/kg; i.p.) selectively reduced the hit rate in GT. Collectively, these findings indicate a limited capacity of ST to sustain attention and suppress competing behaviors. This is a key cognitive trait in individuals vulnerable for addiction, in part because it rapidly exhausts the capacity for filtering drug cues and for attending to alternative task cues and engaging in alternative behavior
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