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

Avila, Cassandra / Sarter, Martin

bioRxiv : the preprint server for biology

2024

Abstract: Turning on cue or stopping at a red light requires the detection of such cues to select action sequences, or suppress action, in accordance with cue-associated action rules. Cortico-striatal projections are an essential part of the brain's attention- ... ...

Abstract	Turning on cue or stopping at a red light requires the detection of such cues to select action sequences, or suppress action, in accordance with cue-associated action rules. Cortico-striatal projections are an essential part of the brain's attention-motor interface. Here, we used glutamate-sensing microelectrode arrays to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic-DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns, and initiated such turns more slowly, than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In conjunction with turn cue-evoked glutamate spike levels, the presence of a single spike rendered GTs to be almost twice as likely to turn than STs. In contrast, multiple glutamate spikes predicted STs to be robustly more likely to turn than GTs. In GTs, inhibition of prelimbic-DMS projections attenuated turn rates and turn cue-evoked glutamate peaks and increased the number of spikes. These findings suggest that turn cue-evoked glutamate release dynamics in GTs are tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals is regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking.
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.12.584623
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Article ; Online: Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071.

Kucinski, Aaron / Sarter, Martin

Psychopharmacology

2021 Volume 238, Issue 7, Page(s) 1953–1964

Abstract: 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 ... ...

Abstract	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. Objectives: We previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats. Results: Prior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. As before, DL rats fell more frequently than sham-operated control rats. Treatment of DL rats with TAK-071 reduced falls from the rotating rod and the rotating zigzag rod, specifically when the angled part of the zigzag segment, upon entering, was at a steep, near vertical angle. Conclusions: TAK-071 may benefit complex movement control, specifically in situations which disrupt the patterning of forward movement and require the interplay between cognitive and motor functions to modify movement based on information about the state of dynamic surfaces, balance, and gait.
MeSH term(s)	Accidental Falls/prevention & control ; Administration, Oral ; Allosteric Regulation/drug effects ; Allosteric Regulation/physiology ; Animals ; Basal Forebrain/drug effects ; Basal Forebrain/metabolism ; Cholinergic Neurons/drug effects ; Cholinergic Neurons/metabolism ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Dopamine/metabolism ; Female ; Muscarinic Agonists/pharmacology ; Muscarinic Agonists/therapeutic use ; Oxidopamine/toxicity ; Parkinsonian Disorders/chemically induced ; Parkinsonian Disorders/drug therapy ; Parkinsonian Disorders/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Muscarinic M1/agonists ; Receptor, Muscarinic M1/metabolism
Chemical Substances	Muscarinic Agonists ; Receptor, Muscarinic M1 ; Oxidopamine (8HW4YBZ748) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2021-03-18
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-021-05822-x
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Article ; Online: Basal Forebrain Chemogenetic Inhibition Converts the Attentional Control Mode of Goal-Trackers to That of Sign-Trackers.

Kucinski, Aaron / Avila, Cassandra / Sarter, Martin

eNeuro

2022 Volume 9, Issue 6

Abstract: 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 ...

Abstract	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). Upon reaching asymptotic performance in an operant task requiring the detection of visual signals (hits) as well as the reporting of signal absence for 40 min per session, GTs scored more hits than STs, and hit rates across all phenotypes correlated with PCA scores. STs missed relatively more signals than GTs specifically during the last 15 min of a session. Chemogenetic inhibition of the basal forebrain decreased hit rates in GTs but was without effect in STs. Moreover, the decrease in hits in GTs manifested solely during the last 15 min of a session. Transfection efficacy in the horizontal limb of the diagonal band (HDB), but not substantia innominate (SI) or nucleus basalis of Meynert (nbM), predicted the behavioral efficacy of chemogenetic inhibition in GTs. Furthermore, the total subregional transfection space, not transfection of just cholinergic neurons, correlated with performance effects. These results indicate that the cognitive-behavioral phenotype indexed by goal tracking, but not sign tracking, depends on activation of the basal forebrain-frontal cortical projection system and associated biases toward top-down or model-based performance.
MeSH term(s)	Rats ; Male ; Female ; Animals ; Goals ; Rats, Sprague-Dawley ; Cues ; Basal Forebrain/physiology ; Motivation
Language	English
Publishing date	2022-12-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0418-22.2022
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Article: Behavioral-Cognitive Targets for Cholinergic Enhancement.

Sarter, Martin

Current opinion in behavioral sciences

2015 Volume 4, Page(s) 22–26

Abstract: Cholinergic mechanisms have long been considered a promising target for enhancing cognitive functions. Two distinct yet interacting components of cholinergic activity have been proposed to mediate specific cognitive functions. Transient spikes in ... ...

Abstract	Cholinergic mechanisms have long been considered a promising target for enhancing cognitive functions. Two distinct yet interacting components of cholinergic activity have been proposed to mediate specific cognitive functions. Transient spikes in cholinergic activity mediate the detection of cues in situations involving attentional mode shifts. More slowly changing cholinergic neuromodulation of cortical circuitry regulates task compliance specifically in response to performance challenges. Increases in cholinergic neuromodulation enhances the generation of cholinergic transients via stimulation of α4β2* nicotinic acetylcholine receptors. Stimulation of these receptors stabilizes attentional performance and increases cue detection rates. Adjunctive treatment with agonists or modulators at these receptors is predicted to benefit unstable attentional performance and low cue detection rates that are common to several brain disorders.
Language	English
Publishing date	2015-01-15
Publishing country	Netherlands
Document type	Journal Article
ISSN	2352-1546
ISSN	2352-1546
DOI	10.1016/j.cobeha.2015.01.004
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Book: Benzodiazepine receptor inverse agonists

Sarter, Martin

1995

Author's details	ed. Martin Sarter
Keywords	Receptors, GABA-A / antagonists & inhibitors ; Receptors, GABA-A / metabolism ; Benzodiazepinrezeptor ; Agonist
Subject	Synergist ; Mimetikum
Language	English
Size	X, 304 S. : graph. Darst.
Publisher	Wiley-Liss
Publishing place	New York u.a.
Publishing country	United States
Document type	Book
HBZ-ID	HT006827236
ISBN	0-471-56173-8 ; 978-0-471-56173-6
Database	Catalogue ZB MED Medicine, Health

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1995 A 5099	order for loan	Magazin

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

Sarter, Martin / Lustig, Cindy

The Journal of neuroscience : the official journal of the Society for Neuroscience

2020 Volume 40, Issue 4, Page(s) 712–719

Abstract: 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 ... ...

Abstract	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. We describe an alternative view by which forebrain signaling in cortex driving cognition is largely phasic (milliseconds to perhaps seconds), and unlikely to be volume-transmitted. This alternative is supported by new evidence from real-time amperometric recordings of cholinergic signaling indicating a specific function of rapid, phasic, transient cholinergic signaling in attentional contexts. Previous neurochemical evidence may be reinterpreted in terms of integrated phasic cholinergic activity that mediates specific behavioral and cognitive operations; this reinterpretation fits well with recent computational models. Optogenetic studies support a causal relationship between cholinergic transients and behavior. This occurs in part via transient-evoked muscarinic receptor-mediated high-frequency oscillations in cortical regions. Such oscillations outlast cholinergic transients and thus link transient ACh signaling with more sustained postsynaptic activity patterns to support relatively persistent attentional biases. Reconceptualizing cholinergic function as spatially specific, phasic, and modulating specific cognitive operations is theoretically powerful and may lead to pharmacologic treatments more effective than those based on traditional views.
MeSH term(s)	Animals ; Cholinergic Neurons/physiology ; Humans ; Prosencephalon/physiology ; Receptors, Muscarinic/physiology ; Receptors, Nicotinic/physiology ; Signal Transduction/physiology ; Synaptic Transmission/physiology
Chemical Substances	Receptors, Muscarinic ; Receptors, Nicotinic
Language	English
Publishing date	2020-01-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1305-19.2019
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Zs.A 1668: Show issues

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

Phillips, Kyra B / Sarter, Martin

Behavioral neuroscience

2020 Volume 134, Issue 2, Page(s) 133–143

Abstract: 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 ...

Abstract	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. Here we addressed the possibility that STs and GTs employ fundamentally different psychological mechanisms for the detection of cues in attention-demanding contexts. Rats were trained to perform an operant Sustained Attention Task. As task training advanced to the stage that taxed attentional control, the relative brightness of visual target signals significantly influenced detection performance in STs but not GTs. This finding suggests that STs, but not GTs, rely on bottom-up, cue salience-driven mechanisms to detect cues. GTs may be able to resist behavioral control by Pavlovian drug cues by utilizing goal-directed decisional processes that minimize the influence of the salience of drug cues. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
MeSH term(s)	Animals ; Attention ; Behavior, Addictive/psychology ; Behavior, Animal ; Choice Behavior ; Conditioning, Operant ; Cues ; Female ; Goals ; Male ; Photic Stimulation ; Rats, Sprague-Dawley ; Visual Perception
Language	English
Publishing date	2020-01-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	230159-3
ISSN	1939-0084 ; 0735-7044
ISSN (online)	1939-0084
ISSN	0735-7044
DOI	10.1037/bne0000353
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Article ; Online: Comment on Pohorala et al.: Sign-tracking as a predictor of addiction vulnerability.

Flagel, Shelly B / Robinson, Terry E / Sarter, Martin

Psychopharmacology

2021 Volume 238, Issue 9, Page(s) 2661–2664

MeSH term(s)	Behavior, Addictive ; Reward
Language	English
Publishing date	2021-07-26
Publishing country	Germany
Document type	Letter ; Comment
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-021-05927-3
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Article ; Online: Neuro-Immune Modulation of Cholinergic Signaling in an Addiction Vulnerability Trait.

Carmon, Hanna / Haley, Evan C / Parikh, Vinay / Tronson, Natalie C / Sarter, Martin

eNeuro

2023 Volume 10, Issue 3

Abstract: 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, ... ...

Abstract	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. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here, we investigated a posttranslational modification of CHTs, poly-ubiquitination, and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines measured in cortex and striatum, but not spleen, were higher in STs than in GTs. Activation of the innate immune system by systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) elevated ubiquitinated CHT levels in cortex and striatum of GTs only, suggesting ceiling effects in STs. In spleen, LPS increased levels of most cytokines in both phenotypes. In cortex, LPS particularly robustly increased levels of the chemokines CCL2 and CXCL10. Phenotype-specific increases were restricted to GTs, again suggesting ceiling effects in STs. These results indicate that interactions between elevated brain immune modulator signaling and CHT regulation are essential components of the neuronal underpinnings of the addiction vulnerability trait indexed by sign-tracking.
MeSH term(s)	Rats ; Male ; Female ; Animals ; Rats, Sprague-Dawley ; Cues ; Lipopolysaccharides/pharmacology ; Motivation ; Cholinergic Agents/pharmacology ; Phenotype ; Reward
Chemical Substances	Lipopolysaccharides ; Cholinergic Agents
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0023-23.2023
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Article ; Online: Cholinergic double duty: cue detection and attentional control.

Sarter, Martin / Lustig, Cindy

Current opinion in psychology

2019 Volume 29, Page(s) 102–107

Abstract: 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 ... ...

Abstract	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. Evidence from humans expressing genetic variants of the choline transporter as well as from patients with degenerating cholinergic systems supports the hypothesis that attentional control capacities depend on levels of cholinergic neuromodulation. Deficits in cholinergic-attentional control impact diverse cognitive functions, including timing, working memory, and complex movement control.
MeSH term(s)	Acetylcholine/physiology ; Animals ; Attention/physiology ; Brain ; Cerebral Cortex/physiology ; Cognition/physiology ; Cues ; Humans ; Mice ; Rats
Chemical Substances	Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2019-01-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2831565-0
ISSN	2352-2518 ; 2352-250X ; 2352-250X
ISSN (online)	2352-2518 ; 2352-250X
ISSN	2352-250X
DOI	10.1016/j.copsyc.2018.12.026
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