Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback

Hangya, Balázs; Ranade, Sachin; Lorenc, Maja; Kepecs, Ádám

doi:10.1016/j.cell.2015.07.057

Cited by 361 publications

(494 citation statements)

References 58 publications

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“…Towards this end we suggest two, not mutually-exclusive principles: 1) segregated inputs to the BFc convey specific cognitive operations and overlapping, common inputs mediate state-related changes; alternatively, 2) the complex set of inputs described in our study reflect multiple inbuilt templates for flexible control of cortical states in a modality-specific fashion via the tonic and phasic firing of cholinergic neurons (Hangya et al, 2015; Harrison et al, 2016). …”

Section: Discussionmentioning

confidence: 86%

The Input-Output Relationship of the Cholinergic Basal Forebrain

2017

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Summary Basal forebrain cholinergic neurons influence cortical state, plasticity, learning and attention. They collectively innervate the entire cerebral cortex, differentially controlling acetylcholine efflux across different cortical areas and timescales. Such control might be achieved by differential inputs driving separable cholinergic outputs, although no input-output relationship on a brain-wide level has ever been demonstrated. Here we identify input neurons to cholinergic cells projecting to specific cortical regions by infecting cholinergic axon terminals with a monosynaptically-restricted viral tracer. This approach revealed several circuit motifs, such as central amygdala neurons synapsing onto basolateral amygdala-projecting cholinergic neurons or strong somatosensory cortical input to motor cortex-projecting cholinergic neurons. The presence of input cells in the parasympathetic midbrain nuclei contacting frontally projecting cholinergic neurons suggest that the network regulating the inner eye muscles are additionally regulating cortical state via acetylcholine efflux. This dataset enables future circuit-level experiments to identify drivers of known cholinergic cortical functions.

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Section: Discussionmentioning

confidence: 86%

The Input-Output Relationship of the Cholinergic Basal Forebrain

2017

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“…This hypothesis predicts that the loss of reward caused by distractors and associated error rates alters the likelihood for, and perhaps also the dynamics of, cholinergic transients. It also predicts that in subjects with reduced motivation to perform, or otherwise aberrant mesolimbic signaling, the presence and timing of transients could be sufficiently altered to yield impaired cognitive performance, including the maladaptive learning of cue-reward relationships (17).…”

Section: Discussionmentioning

confidence: 99%

“…Such an anatomical organization favors hypotheses describing the cholinergic mediation of discrete cognitive-behavioral processes. Studies assessing the behavioral effects of cholinergic lesions, recording from or stimulating BF neurons in behaving animals have supported such hypotheses, proposing that cholinergic activity enhances sensory coding and mediates the ability of reward-predicting stimuli to control behavior (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

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confidence: 94%

Cortical cholinergic signaling controls the detection of cues

Gritton

Howe

Mallory

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

166

208

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The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.V irtually all cortical regions and layers receive inputs from cholinergic neurons originating in the nucleus basalis of Meynert, the substantia innominata, and the diagonal band of the basal forebrain (BF). Reflecting the seemingly diffuse organization of this projection system, functional conceptualizations traditionally have described acetylcholine (ACh) as a neuromodulator that influences broadly defined behavioral and cognitive processes such as wakefulness, arousal, and gating of input processing (1, 2). However, anatomical studies have revealed a topographic organization of BF cholinergic cell bodies with highly segregated cortical projection patterns (3-7). Such an anatomical organization favors hypotheses describing the cholinergic mediation of discrete cognitive-behavioral processes. Studies assessing the behavioral effects of cholinergic lesions, recording from or stimulating BF neurons in behaving animals have supported such hypotheses, proposing that cholinergic activity enhances sensory coding and mediates the ability of reward-predicting stimuli to control behavior (8-17).In separate experiments using two different tasks, we reported the presence of phasic cholinergic release events (transients) in the medial prefrontal cortex (mPFC) of rodents trained to report the presence of cues (18,19). These studies used choline-sensitive microelectrodes to measure changes in extracellular choline concentrations that reflect the hydrolysis of newly released ACh by endogenous acetylcholinesterase (SI Results and Discussion). Importantly, such cholinergic transients were not observed in trials in which cues were missed and in which the absence of a cue was correctly reported and rewarded. Cho...

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“…Alertness is also an essential permissive signal for the orienting and executive aspects of attention (Robbins, 1997; Harris and Thiele, 2011; Petersen and Posner, 2012) and may influence other multifaceted internal states and behaviors (Pfaff et al, 2008; Anderson, 2016). The noradrenergic locus coeruleus has been implicated as a critical mediator of alertness (reviewed in Aston-Jones and Cohen, 2005), with some evidence for the role of basal forebrain cholinergic cells (Harris and Thiele, 2011; Lee and Dan, 2012; Pinto et al, 2013; Hangya et al, 2015; Reimer et al, 2016). However, unlike with sleep/wake states, the contributions of most other neuromodulatory systems to alertness have not yet been explored to test hypotheses for potential alternative sources of neuromodulation (Marrocco et al, 1994; Robbins, 1997).…”

Section: Introductionmentioning

confidence: 99%

Ancestral Circuits for the Coordinated Modulation of Brain State

Lovett-Barron¹,

Andalman²,

Allen³

et al. 2017

Cell

146

144

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SUMMARY Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.

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Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback

Cited by 361 publications

References 58 publications

The Input-Output Relationship of the Cholinergic Basal Forebrain

The Input-Output Relationship of the Cholinergic Basal Forebrain

Cortical cholinergic signaling controls the detection of cues

Ancestral Circuits for the Coordinated Modulation of Brain State

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