Cortico-striatal action control inherent of opponent cognitive-motivational styles.

Unlabelled: Turning on cue or stopping at a red light requires attending to such cues to select action sequences, or suppress action, in accordance with learned cue-associated action rules. Cortico-striatal projections are an essential part of the brain's attention-motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops.

Neuro-Immune Modulation of Cholinergic Signaling in an Addiction Vulnerability Trait.

Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking.

Basal Forebrain Chemogenetic Inhibition Converts the Attentional Control Mode of Goal-Trackers to That of Sign-Trackers.

Sign tracking versus goal tracking in rats indicate vulnerability and resistance, respectively, to Pavlovian cue-evoked addictive drug taking and relapse. Here, we tested hypotheses predicting that the opponent cognitive-behavioral styles indexed by sign tracking versus goal tracking include variations in attentional performance which differentially depend on basal forebrain projection systems. Pavlovian Conditioned Approach (PCA) testing was used to identify male and female sign-trackers (STs) and goal-trackers (GTs), as well as rats with an intermediate phenotype (INTs).

Cholinergic systems, attentional-motor integration, and cognitive control in Parkinson's disease.

Dysfunction and degeneration of CNS cholinergic systems is a significant component of multi-system pathology in Parkinson's disease (PD). We review the basic architecture of human CNS cholinergic systems and the tools available for studying changes in human cholinergic systems. Earlier post-mortem studies implicated abnormalities of basal forebrain corticopetal cholinergic (BFCC) and pedunculopontine-laterodorsal tegmental (PPN-LDT) cholinergic projections in cognitive deficits and gait-balance deficits, respectively.

Disrupted Choline Clearance and Sustained Acetylcholine Release by a Common Choline Transporter Coding Variant Associated with Poor Attentional Control in Humans.

Transport of choline via the neuronal high-affinity choline transporter (CHT; ) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional control as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed, , CHT-mediated choline transport, and ACh release.

Theta-gamma coupling emerges from spatially heterogeneous cholinergic neuromodulation.

Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation.

α4β2 Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

Objective: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4β2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4β2* nAChR partial agonist varenicline.

Methods: Nondemented PD participants with cholinergic deficits were identified with [ F]fluoroethoxybenzovesamicol positron emission tomography (PET).

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071.

Rationale: In addition to the disease-defining motor symptoms, patients with Parkinson's disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine (DA) loss, to the resulting disruption of the attentional control of balance and complex movements. Rats with dual cholinergic-DA losses ("DL rats") were previously demonstrated to model PD falls and associated impairments of gait and balance.

Make a Left Turn: Cortico-Striatal Circuitry Mediating the Attentional Control of Complex Movements.

Background: In movement disorders such as Parkinson's disease (PD), cholinergic signaling is disrupted by the loss of basal forebrain cholinergic neurons, as well as aberrant activity in striatal cholinergic interneurons (ChIs). Several lines of evidence suggest that gait imbalance, a key disabling symptom of PD, may be driven by alterations in high-level frontal cortical and cortico-striatal processing more typically associated with cognitive dysfunction.

Methods: Here we describe the corticostriatal circuitry that mediates the cognitive-motor interactions underlying such complex movement control.

Complex Movement Control in a Rat Model of Parkinsonian Falls: Bidirectional Control by Striatal Cholinergic Interneurons.

Older persons and, more severely, persons with Parkinson's disease (PD) exhibit gait dysfunction, postural instability and a propensity for falls. These dopamine (DA) replacement-resistant symptoms are associated with losses of basal forebrain and striatal cholinergic neurons, suggesting that falls reflect disruption of the corticostriatal transfer of movement-related cues and their striatal integration with movement sequencing. To advance a rodent model of the complex movement deficits of Parkinsonian fallers, here we first demonstrated that male and female rats with dual cortical cholinergic and striatal DA losses (DL rats) exhibit cued turning deficits, modeling the turning deficits seen in these patients.

Phasic cholinergic signaling promotes emergence of local gamma rhythms in excitatory-inhibitory networks.

Recent experimental results have shown that the detection of cues in behavioral attention tasks relies on transient increases of acetylcholine (ACh) release in frontal cortex and cholinergically driven oscillatory activity in the gamma frequency band (Howe et al. Journal of Neuroscience, 2017, 37, 3215). The cue-induced gamma rhythmic activity requires stimulation of M1 muscarinic receptors.

Forebrain Cholinergic Signaling: Wired and Phasic, Not Tonic, and Causing Behavior.

Conceptualizations of cholinergic signaling as primarily spatially diffuse and slow-acting are based largely on measures of extracellular brain ACh levels that require several minutes to generate a single data point. In addition, most such studies inhibited the highly potent catalytic enzyme for ACh, AChE, to facilitate measurement of ACh. Absent such inhibition, AChE limits the presence of ambient ACh and thus renders it unlikely that ACh influences target regions via slow changes in extracellular ACh concentrations.

Addiction vulnerability and the processing of significant cues: Sign-, but not goal-, tracker perceptual sensitivity relies on cue salience.

The identification of broadly defined psychological traits that bestow vulnerability for the manifestation of addiction-like behaviors can guide the discovery of the neuronal mechanisms underlying the propensity for drug taking. Sign-tracking behavior in rats (STs) signifies the presence of a trait that predicts a relatively greater behavioral control of Pavlovian drug and reward cues than in rats that exhibit goal-tracking behavior (GTs). We previously demonstrated that relatively poor cholinergic-attentional control in STs is an essential component of the trait indexed by sign-tracking and that this trait aspect contributes to the relatively greater power of drug cues to control the behavior of STs.

Correction to: Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

After publication of this paper, the authors determined that the "Acknowledgments" section was omitted. Below is the "Acknowledgments" statement.

Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071.

Rationale: Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and, in patients with Parkinson's disease (PD), to impairments in gait and balance and the resulting risks for falls. Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments.

Objectives: Here, we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance.

The paraventricular thalamus is a critical mediator of top-down control of cue-motivated behavior in rats.

Cues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the sign-tracker/goal-tracker animal model. Goal-trackers attribute predictive value to reward-cues, and sign-trackers attribute both predictive and incentive value.

Repetitive mild concussion in subjects with a vulnerable cholinergic system: Lasting cholinergic-attentional impairments in CHT+/- mice.

Previous research emphasized the impact of traumatic brain injury on cholinergic systems and associated cognitive functions. Here we addressed the converse question: Because of the available evidence indicating cognitive and neuronal vulnerabilities in humans expressing low-capacity cholinergic systems or with declining cholinergic systems, do injuries cause more severe cognitive decline in such subjects, and what cholinergic mechanisms contribute to such vulnerability? Using mice heterozygous for the choline transporter (CHT+/- mice) as a model for a limited cholinergic capacity, we investigated the cognitive and neuronal consequences of repeated, mild concussion injuries (rmCc). After five rmCc, and compared with wild type (WT) mice, CHT+/- mice exhibited severe and lasting impairments in sustained attention performance, consistent with effects of cholinergic losses on attention.

Cholinergic double duty: cue detection and attentional control.

Cholinergic signaling in the cortex involves fast or transient signaling as well as a relatively slower neuromodulatory component. These two components of cholinergic activity mediate separate yet interacting aspects of cue detection and attentional control. The transient component appears to support the activation of cue-associated task or response sets, whereas the slower modulatory component stabilizes task-set and context representations, therefore potentially facilitating top-down control.

Basal forebrain chemogenetic inhibition disrupts the superior complex movement control of goal-tracking rats.

Sign- and goal-tracking behavior signifies the influence of opposed cognitive-motivational styles, with the former being characterized by a tendency for approaching and contacting reward cues, including a readiness for attending, bottom-up, to salient cues, and a relatively greater vulnerability for developing and maintaining addiction-like behaviors. We previously demonstrated that these styles also impact the cognitive-motor interactions that are taxed during traversal of dynamic surfaces, with goal-trackers (GTs) making less movement errors and falling less frequently than sign-trackers (STs). The present experiment tested the hypothesis that complex movement control in GTs, but not STs, depends on activation of the basal forebrain projection system to telencephalic regions.

Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

Rationale: Falls in patients with Parkinson's disease (PD) are associated with cognitive, specifically attentional impairments and with losses in cholinergic projection systems. We previously established an animal model of the combined basal forebrain cholinergic-striatal dopaminergic losses of PD fallers (Dual Lesioned, DL, rats) and demonstrated that treating DL rats with an acetylcholinesterase inhibitor (AChEI), donepezil, together with a 5HT receptor antagonist, idalopirdine, reduced fall frequency and improved associated aspects of the performance of DL rats traversing rotating rods.

Objectives: Here, we employed a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with the pseudo-irreversible, and thus relatively long-acting, AChE- and butyrylcholinesterase- (BuChE) inhibitor rivastigmine.

Regional vesicular acetylcholine transporter distribution in human brain: A [ F]fluoroethoxybenzovesamicol positron emission tomography study.

Prior efforts to image cholinergic projections in human brain in vivo had significant technical limitations. We used the vesicular acetylcholine transporter (VAChT) ligand [ F]fluoroethoxybenzovesamicol ([ F]FEOBV) and positron emission tomography to determine the regional distribution of VAChT binding sites in normal human brain. We studied 29 subjects (mean age 47 [range 20-81] years; 18 men; 11 women).

The hot 'n' cold of cue-induced drug relapse.

Environmental cues associated with rewards can acquire motivational properties. However, there is considerable variation in the extent to which a reward cue gains motivational control over behavior, depending on the individual and the form of the cue. When a discrete cue is paired with food reward, it acquires greater control over motivated behavior in some rats (sign-trackers, STs) than others (goal-trackers, GTs) as indicated by the propensity to approach the cue, the willingness to work to obtain it, and its ability to reinstate reward-seeking behavior.

Addiction vulnerability trait impacts complex movement control: Evidence from sign-trackers.

Cognitive-motivational vulnerability traits are associated with increased risk for substance addiction and relapse. Sign-tracking (ST) behavior in rats is associated with poor attentional control, mediated by an unresponsive basal forebrain cholinergic system, and an increased risk for substance addiction/relapse. A separate literature links poor attentional control and cholinergic losses to increased fall risk in Parkinson's disease.